Amide derivatives

ABSTRACT

The invention concerns amide derivatives of the Formula I                    
     wherein X is CH or N; Y is CH or N; m is 0-3; R 1  is a group such as hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy and carbamoyl; n is 0-3; R 2  is a group such as hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy and (1-6C)alkoxycarbonyl; R 3  is hydrogen, halogeno, (1-6C)alkyl or (1-6C)alkoxy; q is 0-4; and Q is a group such as aryl, aryloxy, aryl-(1-6C)alkoxy, arylamino,  N -(1-6C)alkyl-arylamino and aryl-(1-6C)alkylamino; or pharmaceutically-acceptable salts or in-vivo-cleavable esters thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.

This application is the National Phase of International ApplicationPCT/GB00/00914 filed Mar. 13, 2000 which designated the U.S. and thatInternational Application was published under PCT Article 21(2)inEnglish.

This invention concerns certain amide derivatives which are useful asinhibitors of cytokine mediated disease. The invention also concernsprocesses for the manufacture of the amide derivatives of the invention,pharmaceutical compositions containing them and their use in therapeuticmethods, for example by virtue of inhibition of cytokine mediateddisease.

The amide derivatives disclosed in the present invention are inhibitorsof the production of cytokines such as Tumour Necrosis Factor(hereinafter TNF), for example TNFα, and various members of theinterleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8.Accordingly the compounds of the invention will be useful in thetreatment of diseases or medical conditions in which excessiveproduction of cytokines occurs, for example excessive production of TNFαor IL-1. It is known that cytokines are produced by a wide variety ofcells such as monocytes and macrophages and that they give rise to avariety of physiological effects which are believed to be important indisease or medical conditions such as inflammation and immunoregulation.For example, TNFα and IL-1 have been implicated in the cell signallingcascade which is believed to contribute to the pathology of diseasestates such as inflammatory and allergic diseases and cytokine-inducedtoxicity. It is also known that, in certain cellular systems. TNFαproduction precedes and mediates the production of other cytokines suchas IL-1.

Abnormal levels of cytokines have also been implicated in, for example,the production of physiologically-active eicosanoids such as theprostaglandins and leukotrienes, the stimulation of the release ofproteolytic enzymes such as collagenase, the activation of the immunesystem, for example by stimulation of T-helper cells, the activation ofosteoclast activity leading to the resorption of calcium, thestimulation of the release of proteoglycans from, for example,cartilage, the stimulation of cell proliferation and to angiogenesis.

Cytokines are also believed to be implicated in the production anddevelopment of disease states such as inflammatory and allergicdiseases, for example inflammation of the joints (especially rheumatoidarthritis, osteoarthritis and gout), inflammation of thegastrointestinal tract (especially inflammatory bowel disease,ulcerative colitis, Crohn's disease and gastritis), skin disease(especially psoriasis, eczema and dermatitis) and respiratory disease(especially asthma, bronchitis, allergic rhinitis, adult respiratorydistress syndrome and chronic obstructive pulmonary disease), and in theproduction and development of various cardiovascular and cerebrovasculardisorders such as congestive heart failure, myocardial infarction, theformation of atherosclerotic plaques, hypertension, plateletaggregation, angina, stroke, Alzheimer's disease, reperfusion injury,vascular injury including restenosis and peripheral vascular disease,and, for example, various disorders of bone metabolism such asosteoporosis (including senile and postmenopausal osteoporosis), Paget'sdisease, bone metastases, hypercalcaemia, hyperparathyroidism,osteoscierosis, osteoperosis and periodontitis, and the abnormal changesin bone metabolism which may accompany rheumatoid arthritis andosteoarthritis. Excessive cytokine production has also been implicatedin mediating certain complications of bacterial, fungal and/or viralinfections such as endotoxic shock, septic shock and toxic shocksyndrome and in mediating certain complications of CNS surgery or injurysuch as neurotrauma and ischaemic stroke. Excessive cytokine productionhas also been implicated in mediating or exacerbating the development ofdiseases involving cartilage or muscle resorption, pulmonary fibrosis,cirrhosis, renal fibrosis, the cachexia found in certain chronicdiseases such as malignant disease and acquired immune deficiencysyndrome (AIDS), tumour invasiveness and tumour metastasis and multiplesclerosis.

Evidence of the central role played by TNFα in the cell signallingcascade which gives rise to rheumatoid arthritis is provided by theefficacy in clinical studies of antibodies of TNFα (The Lancet, 1994,344, 1125 and British Journal of Rheumatolgy, 1995, 34, 334).

Thus cytokines such as TNFα and IL-1 are believed to be importantmediators of a considerable range of diseases and medical conditions.Accordingly it is expected that inhibition of the production of and/oreffects of these cytokines will be of benefit in the prophylaxis,control or treatment of such diseases and medical conditions.

Without wishing to imply that the compounds disclosed in the presentinvention possess pharmacological activity only by virtue of an effecton a single biological process, it is believed that the compoundsinhibit the effects of cytokines by virtue of inhibition of the enzymep38 kinase. p38 kinase, otherwise known as cytokine suppressive bindingprotein (hereinafter CSBP) and reactivating kinase (hereinafter RK), isa member of the mitogen-activated protein (hereinafter MAP) kinasefamily of enzymes which is known to be activated by physiological stresssuch as that induced by ionising radiation, cytotoxic agents, andtoxins, for example endotoxins such as bacterial lipopolysaccharide, andby a variety of agents such as the cytokines, for example TNFα A andIL-1. It is known that p38 kinase phosphorylates certain intracellularproteins which are involved in the cascade of enzymatic steps whichleads to the biosynthesis and excretion of cytokines such as TNFα andIL-1. Known inhibitors of p38 kinase have been reviewed by G J Hanson inExpert Opinions on Therapeutic Patents, 1997, 7, 729-733. p38 kinase isknown to exist in isoforms identified as p38α and p38β.

The compounds disclosed in the present invention are inhibitors of theproduction of cytokines such as TNF, in particular of TNFα, and variousinterleukins, in particular IL-1.

According to a first aspect of the present invention there is provided acompound of the Formula I

wherein

X is CH or N;

Y is CH or N;

m is 0, 1, 2 or 3;

R¹ is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphony(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alky]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl,(1-6C)alkoxycarbonyl-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkyl,carbamoyl-(1-6C)alkyl, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl,halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy,cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy,(1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbamoyl-(1-6C)alkoxy,N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy,(1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-6C)alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino,carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino,(1-6C)alkylamino-(2-6C)alkylamino,di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkyl-halogeno-(1-6C)alkylamino,N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,N-(1-6C)alkyl-cyano-(1-6C)alkylamino,N-(1-6C)alkyl-carboxy-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino,N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino,N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,N-(1-6C)alkyl-amino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino,halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino,(1-6C)alkoxy-(2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino,carboxy-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino,carbamoyl-(2-6C)alkanoylamino,N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino,N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino,amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino ordi-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, or R¹ is aryl,aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy, arylamino,N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino,N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino, arylsulphonylamino,N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, heteroaryl,heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl-(1-6C)alkoxy,heteroarylamino, N-(1-6C)alkyl-heteroarylamino,heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino,heteroaryl-(1-6C)alkoxy-(1-6C)alkyl,heteroaryl-(1-6C)alkylamino-(1-6C)alkyl,N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl,heterocyclyl-(1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy,heterocyclylamino, N-(1-6C)alkyl-heterocyclylamino,heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino, heterocyclylcarbonylamino,heterocycylsulphonylamino, N-heterocyclylsulphamoy,heterocyclyl-(2-6C)alkanoylamino, heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl,heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl orN-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl, or (R¹)_(m) isa (1-3C)alkylenedioxy group, and wherein any of the R¹ substituentsdefined hereinbefore which comprises a CH₂ group which is attached to 2carbon atoms or a CH₃ group which is attached to a carbon atom mayoptionally bear on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino and heterocyclyl, and wherein any aryl, heteroarylor heterocyclyl group in a R¹ substituent may optionally bear 1 or 2substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy,carboxy, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryland aryl-(1-6C)alkyl,

n is 0, 1, 2 or 3;

R² is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino or di-[(1-6C)alkyl]amino;

R³ is hydrogen, halogeno, (1-6C)alkyl or (1-6C)alkoxy;

q is 0, 1, 2, 3 or 4; and

Q is aryl, aryloxy, aryl-(1-6C)alkoxy, arylamino,N-(1-6C)alkyl-arylammo, aryl-(1-6C)alkylamino,N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino, arylsulphonylamino,N-arylcarbamoyl, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino,(3-7C)cycloalkyl, heteroaryl, heteroaryloxy, heteroaryl-(1-6C)alkoxy,heteroarylamino, N-(1-6C)alkyl-heteroarylamino,heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylcarbamoyl, N-heteroarylsulphamoyl,heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyloxy,heterocyclyl-(1-6C)alkoxy, heterocyclylamino,N-(1-6C)alkyl-heterocyclylamino, heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylcarbamoyl,N-heterocyclylsulphamoyl or heterocyclyl-(2-6C)alkanoylamino, and Q isoptionally substituted with 1, 2 or 3 substituents selected fromhydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl,(1-6C)alkoxycarbonyl-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy,hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy,carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy,carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy,(1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-6C)alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino,carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino,(1-6C)alkylamino-(2-6C)alkylamino,di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkyl-halogeno-(1-6C)alkylamino,N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,N-(1-6C)alkyl-cyano-(1-6C)alkylamino,N-(1-6C)alkyl-carboxy-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino,N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino,N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino,N-(1-6C)alkyl-amino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino,halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino,(1-6C)alkoxy-(2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino,carboxy-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino,carbamoyl-(2-6C)alkanoylamino,N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino,N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino,amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino,di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl,aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino,aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylaminoarylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino,heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy,heteroaryl-(1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino,heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino,heteroaryl-(1-6C)alkoxy-(1-6C)alkyl,heteroaryl-(1-6C)alkylamino-(1-6C)alkyl,N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl,heterocyclyl-(1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy,heterocyclylamino, N-(1-6C)alkyl-heterocyclylamino,heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylsulphamoyl,heterocyclyl-(2-6C)alkanoylamino, heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl,heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl andN-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl, or Q issubstituted with a (1-3C)alkylenedioxy group, and wherein any of thesubstituents on Q defined hereinbefore which comprises a CH₂ group whichis attached to 2 carbon atoms or a CH₃ group which is attached to acarbon atom may optionally bear on each said CH₂ or CH₃ group asubstituent selected from hydroxy, amino, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl, and whereinany aryl, heteroaryl or heterocyclyl group in a substituent on Q mayoptionally bear 1 or 2 substituents selected from hydroxy, halogeno,(1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl;

or a pharmaceutically-acceptable salt or in-vivo-cleavable esterthereof.

According to a second aspect of the present invention there is provideda compound of the Formula I wherein each of X, Y, R¹, R², m, n, q and Qhave any of the meanings defined hereinbefore and R³ is selected fromhalogeno and (1-6C)alkyl; or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In this specification, the term (1-6C)alkyl includes straight-chain andbranched-chain alkyl groups such as propyl, isopropyl and tert-butyl,and (3-6C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. However references to individual alkyl groups such as“propyl” are specific for the straight-chain version only, references toindividual branched-chain alkyl groups such as “isopropyl” are specificfor the branched-chain version only and references to individualcycloalkyl groups such as “cyclopentyl” are specific for that 5-memberedring only. An analogous convention applies to other generic terms, forexample (1-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy andcyclopentyloxy, (1-6C)alkylamino includes methylamino, ethylamino,cyclobutylamino and cyclohexylamino, and di-[(1-6Calkyl]amino includesdimethylamino, diethylamino, N-cyclobutyl-N-methylamino andN-cyclohexyl-N-ethylamino.

It is to be understood that, insofar as certain of the compounds ofFormula I defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the property of inhibiting cytokines, in particular TNF. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against TNF may beevaluated using the standard laboratory techniques referred tohereinafter.

Suitable values for the generic radicals referred to above include thoseset out below.

A suitable value for R¹ or Q when it is aryl, for a substituent on Qwhen it is aryl or for the aryl group within a R¹ substituent or a Qgroup or within a substituent on Q is, for example, phenyl, indenyl,indanyl, naphthyl, tetrahydronaphthyl or fluorenyl, preferably phenyl.

A suitable value for R¹ or Q when it is heteroaryl, for the heteroarylgroup within a R¹ substituent or a Q group, for a substituent on Q whenit is heteroaryl or for the heteroaryl group within a substituent on Qis, for example, an aromatic 5- or 6-membered monocyclic ring, a 9- or10-membered bicyclic ring or a 13- or 14-membered tricyclic ring eachwith up to five rings heteroatoms selected from oxygen, nitrogen andsulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazoyly pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl,quinolyl, isoquinolyl, quilazolinyl, quinoxalinyl, cinnolinyl,naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl,S,S-dioxodibenzothiophenyl, xanthenyl, dibenzo-1,4-dioxinyl,phenoxathiinyl, phenoxazinyl, dibenzothiinyl, phenothiazinyl,thianthrenyl, benzofuropyridyl, pyridoindolyl, acridinyl orphenanthridinyl, preferably furyl, thienyl, oxazolyl, isoxazolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl,quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,carbazolyl, dibenzofuranyl, dibenzothiophenyl or xanthenyl, morepreferably furyl, thienyl, isoxazolyl, thiazolyl, pyridyl, benzothienyl,benzofurazanyl, quinolyl, carbazolyl, dibenzofuranyl ordibenzothiophenyl.

A suitable value for R¹ or Q when it is heterocyclyl, for a substituenton Q when it is heterocyclyl or for the heterocyclyl group within a R¹substituent or a Q group or within a substituent on Q is, for example, anon-aromatic saturated or partially saturated 3- to 10-memberedmonocyclic or bicyclic ring with up to five heteroatoms selected fromoxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl,azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl,pyrrolidinyl, 1,1-dioxidoisothiazolidinyl, morpholinyl,tetrahydro-1,4-thiazinyl, 1,1-dioxotetrahydro-1,4-thiazinyl,piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl,dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl ortetrahydropyrimidinyl, or, for example, imidazolinyl, imidazolidinyl,pyrazolinyl, pyrazolidinyl, or, for example, benzo derivatives thereofsuch as 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indolinyl,isoindolinyl, chromanyl and isochromanyl, preferably the heterocyclylgroup is pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino,piperazin-1-yl or homopiperazin-1-yl.

A suitable value for Q when it is (3-7C)cycloalkyl is, for example, anon-aromatic mono- or bicyclic 3- to 7-membered carbon ring such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orbicyclo[2.2.1]heptyl, preferably cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl, more preferably cyclohexyl.

Suitable values for various R¹, R² or R³ groups, or for varioussubstituents on Q or on an aryl, heteroaryl or heterocyclyl group withinR¹ or on an aryl, heteroaryl or heterocyclyl group on a substituent on Qinclude:

for halogeno: fluoro, chloro, bromo and iodo;

for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl,cyclobutyl cyclopentyl and cyclohexyl,

for (2-6C)alkenyl: vinyl and allyl;

for (2-6C)alkynyl: ethynyl and 2-propynyl;

for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,butoxy, cyclobutyloxy and cyclopentyloxy;

for (1-6C)alkylamino: methylamino, ethylamino, propylamino,cyclobutylamino and cyclohexylamino;

for di-[(1-6C)alkyl]amino: dimethylamino, diethylamino andN-ethyl-N-methylamino;

for (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl and tert-butoxycarbonyl;

for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl andN-propylcarbamoyl;

for N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl;

for (2-6C)alkanoyl: acetyl and propionyl;

for halogeno-(1-6C)alkyl: fluoromethyl, chloromethyl, bromomethyl,difluoromethyl, dichloromethyl, dibromomethyl, 2-fluoroethyl,2-chloroethyl and 2-bromoethyl;

for hydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyland 3-hydroxypropyl;

for (1-6C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl,1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;

for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and3-cyanopropyl;

for amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and3-aminopropyl;

for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl, ethylaminomethyl,1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and3-methylaminopropyl;

for di-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl,diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and3-dimethylaminopropyl.

Suitable values for R¹ or Q and suitable values for a substituent on R¹or Q include:

for aryl-(1-6C)alkyl: benzyl, 2-phenylethyl, 2-phenylpropyl and3-phenylpropyl:

for aryl-(1-6C)alkoxy: benzyloxy and 2-phenylethoxy;

for aryloxy: phenoxy and 2-naphthyloxy;

for arylamino: anilino;

for N-(1-6C)alkyl-arylamino: N-methylanilino and N-ethylanilino;

for aryl-(1-6C)alkylamino: benzylamino, 2-phenethylamino,2-phenylpropylamino and 3-phenylpropylamino;

for N-(1-6C)alkyl-aryl-(1-6C)alkylamino: N-benzyl-N-methylamino;

for aroylamino: benzamido and 2-naphthoylamino;

arylsulphonylamino: benzenesulphonylamido;

for N-arylcarbamoyl: N-phenylcarbamoyl;

for N-arylsulphamoyl: N-phenylsulphamoyl;

for aryl-(2-6C)alkanoylamino: phenylacetamido and 3-phenylpropionamido;

for heteroaryl-(1-6C)alkyl: heteroarylmethyl, 2-heteroarylethyl,2-heteroarylpropyl and 3-heteroarylpropyl;

for heteroaryl-(1-6C)alkoxy: heteroarylmethoxy and 2-heteroarylethoxy;

for N-(1-6C)alkyl-heteroarylamino: N-methylheteroarylamino;

for heteroaryl-(1-6C)alkylamino: heteroarylmethylamino,2-heteroarylethylamino and 3-heteroarylpropylamino;

for N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino:N-methylheteroarylmethylamino and N-methyl-2-heteroarylethylamino:

for heteroaryl-(2-6C)alkanoylamino: heteroarylacetamido and3-heteroarylpropionamido:

for heteroaryl-(1-6C)alkoxy-(1-6C)alkyl: heteroarylmethoxymethyl,2-heteroarylethoxymethyl and 3-heteroarylpropoxymethyl;

for heteroaryl-(1-6C)alkylamino-(1-6C)alkyl:heteroarylmethylaminomethyl, 2-heteroarylethylaminomethyl and3-heteroarylpropylaminomethyl;

for N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino-(1-6C)alkyl:N-heteroarylmethyl-N-methylaminomethyl,N-(2-heteroarylethyl)-N-methylaminomethyl andN-(3-heteroarylpropyl)-N-methylaminomethyl;

for heterocyclyl-(1-6C)alkyl: heterocyclylmethyl, 2-heterocyclylethyl,2-heterocyclylpropyl and 3-heterocyclylpropyl;

for heterocyclyl-(1-6C)alkoxy: heterocyclylmethoxy and2-heterocyclylethoxy;

for N-(1-6C)alkyl-heterocyclylamino: N-methylheterocyclylamino;

for heterocyclyl-(1-6C)alkylamino: heterocyclylmethylamino,2-heterocyclylethylamino and 3-heterocyclylpropylamino;

for N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino:N-methylheterocyclylmethylamino and N-methyl-2-heterocyclylethylamino;

for heterocyclyl-(2-6C)alkanoylamino: heterocyclylacetamido and3-heterocyclylpropionamido;

for heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl: heterocyclylmethoxymethyl,2-heterocyclylethoxymethyl and 3-heterocyclylpropoxymethyl;

for heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl:heterocyclylmethylaminomethyl, 2-heterocyclylethylaminomethyl and3-heterocyclylethylaminomethyl;

for N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl:N-heterocyclylmethyl-N-methylaminomethyl,N-(2-heterocyclylethyl)-N-methylaminomethyl andN-(3-heterocyclylpropyl)-N-methylaminomethyl;

for (1-3C)alkylenedioxy: methylenedioxy, ethylenedioxy andtrimethylenedioxy;

for (1-6C)alkylthio: methylthio, ethylthio and propylthio;

for (1-6C)alkylsulphinyl: methylsulphinyl, ethylsulphinyl andpropylsulphinyl;

for (1-6C)alkylsulphonyl: methylsulphonyl, ethylsulphonyl andpropylsulplhonyl;

for (2-6C)alkanoyloxy: acetoxy and propionyloxy;

for (1-6C)alkanoylamino: formamido, acetamido and propionamido;

for N-(1-6C)alkylsulphamoyl: N-methylsulphamoyl and N-ethylsulphamoyl;

for N,N-di-[(1-6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl;

for (1-6C)alkanesulphonylamino: methanesulphonylamino andethanesulphonylamino;

for N-(1-6C)alkyl-(1-6C)alkanesulphonylamino:N-methylmethanesulphonylamino and N-methylethanesulphonylamino;

for carboxy-(1-6C)alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl,3-carboxypropyl and 4-carboxybutyl;

for (1-6C)alkoxycarbonyl-(1-6C)alkyl: methoxycarbonylmethyl,ethoxycarbonylmethyl;

tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl,

1-ethoxycarbonylethyl, 2-methoxycarbonylethyl,

2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl and3-ethoxycarbonylpropyl;

for carbamoyl-(1-6C)alkyl: carbamoylmethyl, 1-carbamoylethyl,2-carbamoylethyl and 3-carbamoylpropyl;

for N-(1-6C)alkylcarbamoyl-(1-6C)alkyl: N-methylcarbamoylmethyl,N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl,2-(N-methylcarbamoyl)ethyl 2-(N-ethylcarbamoyl)ethyl and3-(N-methylcarbamoyl)propyl;

for N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl:N,N-dimethylcarbamoylmethyl, N-ethyl-N-methylcarbamoylmethyl,N,N-diethylcarbamoylmethyl, 1-(N,N-dimethylcarbamoyl)ethyl,1-(N,N-diethylcarbamoyl)ethyl, 2-(N,N-dimethylcarbamoyl)ethyl,2-(N,N-diethylcarbamoyl)ethyl, 3-(N,N-dimethylcarbamoyl)propyl and4-(N,N-dimethylcarbamoyl)butyl;

for halogeno-(2-6C)alkoxy: 2-chloroethoxy, 2-bromoethoxy,3-chloropropoxy, 1,1,2,2-tetrafluoroethoxy and 2,2,2-trifluoroethoxy;

for hydroxy-(2-6C)alkoxy: 2-hydroxyethoxy, 3-hydroxypropoxy,2-hydroxy-1-methylethoxy, 2-hydroxy-2-propoxy and 4-hydroxybutoxy;

for (1-6C)alkoxy-(2-6C)alkoxy: 2-methoxyethoxy, 2-ethoxyethoxy,3-methoxypropoxy, 2-methoxy-1-methylethoxy and 4-ethoxybutoxy;

for cyano-(1-6C)alkoxy: cyanomethoxy, 2-cyanoethoxy and 3-cyanopropoxy:

for carboxy-(1-6C)alkoxy: carboxymethoxy, 1-carboxyethoxy,2-carboxyethoxy and 3-carboxypropoxy;

for (1-6C)alkoxycarbonyl-(1-6C)alkoxy: methoxycarbonylmethoxy,ethoxycarbonylmethoxy, tert-butoxycarbonylmethoxy,2-methoxycarbonylethoxy and 3-ethoxycarbonylpropoxy;

for carbamoyl-(1-6C)alkoxy: carbamoylmethoxy and 2-carbamoylethoxy;

for N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy: N-methylcarbamoylmethoxy,2-(N-ethylcarbamoyl)ethoxy and 3-(N-methylcarbamoyl)propoxy;

for N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy:N,N-dimethylcarbamoylmethoxy, 2-(N,N-dimethylcarbamoyl)ethoxy and3-(N,N-diethylcarbamoyl)propoxy;

for amino-(2-6C)alkoxy: 2-aminoethoxy, 2-amino-1-methylethoxy,3-aminopropoxy, 2-amino-2-methylpropoxy and 4-aminobutoxy;

for (1-6C)alkylamino-(2-6C)alkoxy: 2-methylaminoethoxy,2-methylamino-1-methylethoxy and 3-ethylaminopropoxy;

for di-[(1-6C)alkyl]amino-(2-6C)alkoxy: 2-dimethylaminoethoxy,2-diethylaminoethoxy, 2-dimethylaminopropoxy,2-dimethylamino-2-methylethoxy, 3-dimethylaminopropoxy and4-dimethylaminobutoxy;

for halogeno-(2-6C)alkylamino: 2-fluoroethylamino, 2-chloroethylamino,2-bromoethylamino, 3-fluoropropylamino and 3-chloropropylamino;

for hydroxy-(2-6C)alkylamino: 2-hydroxyethylamino, 3-hydroxypropylamino,2-hydroxy-2-methylpropylamino and 4-hydroxybutylamino;

for (1-6C)alkoxy-(2-6C)alkylamino: 2-methloxyethylamino,2-ethoxyethylamino, 3-methoxypropylamino and 3-ethoxypropylamino;

for cyano-(1-6C)alkylamino: cyanomethylamino, 2-cyanoethylamino and3-cyanopropylamino;

for carboxy-(1-6C)alkylamino: carboxymethylamino, 1-carboxyethylamino,2-carboxyethylamino and 3-carboxypropylamino;

for (1-6C)alkoxycarbonyl-(1-6C)alkylamino: methoxycarbonylmethylamino,2-(ethoxycarbonyl)ethylamino and 3-(tert-butoxycarbonyl)propylamino;

for carbamoyl-(1-6C)alkylamino: carbamoylmethylamino and2-carbamoylethylamino;

for N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino:N-methylcarbamoylmethylamino, N-ethylcarbamoylmethylamino and2-(N-methylcarbamoyl)ethylamino;

for N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino:N,N-dimethylcarbamoylmethylamino, N,N-diethylcarbamoylmethylamino and2-(N,N-dimethylcarbamoyl)ethylamino;

for amino-(2-6C)alkylamino: 2-aminoethylamino, 3-aminopropylamino,2-amino-2-methylpropylamino and 4-aminobutylamino;

for (1-6C)alkylamino-(2-6C)alkylamino: 2-methylaminoethylamino,2-ethylaminoethylamino, 2-propylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-methylamino-2-methylpropylamino and 4-methylaminobutylamino;

for di-[(1-6C)alkyl]amino-(2-6C)alkylamino: 2-dimethylaminoethylamino,2-(N-ethyl-N-methylamino)ethyl amino, 2-diethylaminoethylamino,2-dipropylaminoethylamino, 3-dimethylaminopropylamino,3-diethylaminopropylamino, 2-dimethylamino-2-methylpropylamino and4-dimethylaminobutylamino;

for N-(1-6C)alkyl-halogeno-(2-6C)alkylamino:N-(2-chloroethyl)-N-methylamino, N-(2-bromoethyl)-N-methylamino andN-(2-bromoethyl)-N-ethylamino,

for N-(1-6C)alkyl-hydroxy-(2-6C)-alkylamino:N-(2-hydroxyethyl)-N-methylamino, N-(3-hydroxypropyl)-N-methylamino andN-ethyl-N-(2-hydroxyethyl)amino;

for N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino:N-methyl-N-(2-methoxyethyl)amino, N-methyl-N-(3-methoxypropyl)amino andN-ethyl-N-(2-methoxyethyl)amino;

for N-(1-6C)alkyl-cyano-(1-6C)alkylamino: N-(cyanomethyl)-N-methylamino;

for N-(1-6C)alkyl-carboxy-(1-6C)alkylamino:N-carboxymethyl-N-methylamino and N-(2-carboxyethyl)-N-methylamino;

for N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino:N-methoxycarbonylmethyl-N-methylamino,N-(2-ethoxycarbonylethyl)-N-ethylamino andN-(2-tert-butoxycarbonylethyl)-N-methylamino;

for N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino:N-carbamoylmethyl-N-methylamino and N-(2-carbamoylethyl)-N-methylamino;

for N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino:N-(N-methylcarbamoylmethyl)-N-methylamino,N-(N-ethylcarbamoylmethyl)-N-methylamino andN-[2-(N-methylcarbamoyl)ethyl]-N-methylamino;

for N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino:N-(N,N-dimethylcarbamoylmethyl)-N-methylamino andN-[2-(N,N-dimethylcarbamoyl)ethyl]-N-methylamino;

for N-(1-6C)alkyl-amino-(2-6C)alkylamino:N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino andN-(4-aminobutyl)-N-methylamino;

for N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino:N-(2-methylaminoethyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-ethylamino andN-(4-methylaminobutyl)-N-methylamino;

for N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino:N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino andN-(4-dimethylaminobutyl)-N-methylamino;

for halogeno-(2-6C)alkanoylamino: 2-chloroacetamido and3-chloropropionamido;

for hydroxy-(2-6C)alkanoylamino: 2-hydroxyacetamido and3-hydroxypropionamido:

for (1-6C)alkoxy-(2-6C)alkanoylamino: 2-methoxyacetamido and3-methoxypropionamido;

for cyano-(2-6C)alkanoylamino: 2-cyanoacetamido and 3-cyanopropionamido;

for carboxy-(2-6C)alkanoylamino: 2-carboxyacetamido and3-carboxypropionamido;

for (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino:2-methoxycarbonylacetamido, 2-(tert-butoxycarbonyl)acetamido and3-methoxycarbonylpropionamido;

for carbamoyl-(2-6C)alkanoylamino: 2-carbamoylacetamido,3-carbamoylpropionamido and 4-carbamoylbutyramido;

for N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino:2-(N-methylcarbamoyl)acetamido and 3-(N-ethylcarbamoyl)propionamido;

for N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino:2-(N,N-dimethylcarbamoyl)acetamido, 2-(N,N-dimethylcarbamoyl)acetamidoand 3-(N,N-dimethylcarbamoyl)propionamido;

for amino-(2-6C)alkanoylamino: 2-aminoacetamido, 2-aminopropionamido and3-aminopropionamido;

for (1-6C)alkylamino-(2-6C)alkanoylamino: 2-methylaminoacetamido,2-ethylaminoacetamido, 2-methylaminopropionamido and3-methylaminopropionamido;

for di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino: 2-dimethylaminoacetamido,2-diethylaminoacetamido, 2-dimethylaminopropionamido and3-dimethylaminopropionamido.

When, as defined hereinbefore, any of the substituents on R¹ or Q whichcomprises a CH₂ group which is attached to 2 carbon atoms or a CH₃ groupwhich is attached to a carbon atom may optionally bear on each said CH₂or CH₃ group a substituent selected from hydroxy. amino, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl, suitablesubstituents so formed include, for example, substitutedheterocyclyl-(1-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxyand 2-hydroxy-3-morpholinopropoxy, substituted amino-(2-6C)alkoxy groupssuch as 3-amino-2-hydroxypropoxy, substituted(1-6C)alkylamino-(2-6C)alkoxy groups such as2-hydroxy-3-methylaminopropoxy, substituteddi-[(1-6C)alkyl]amino-(2-6C)alkoxy groups such as3-dimethylamino-2-hydroxypropoxy,3-[N-(3-dimethylaminopropyl)-N-methylamino]propoxy and3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropoxy,substituted heterocyclyl-(1-6C)alkylamino groups such as2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino,substituted amino-(2-6C)alkylamino groups such as3-amino-2-hydroxypropylamino, substituted(1-6C)alkylamino-(2-6C)alkylamino groups such as2-hydroxy-3-methylaminopropylamino, substituteddi-[(1-6C)alkyl]amino-(2-6C)alkylamino groups such as3-dimethylamino-2-hydroxypropylamino,3-[N-(3-dimethylaminopropyl)-N-methylamino]propylamino and3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropylamino andsubstituted (1-6C)alkylamino-(1-6C)alkyl groups such as2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-morpholinoethylaminomethyl, 2-piperazin-1-ylethylaminomethyl and3-morpholinopropylaminomethyl.

For the avoidance of any doubt it is to be understood that, when X or Yis a CH group and the ring in which the X and Y groups are embeddedbears one or more R¹ substituents, a R¹ substituent may be located atany suitable location on that ring including on the carbon atom at the Xor Y position.

A suitable pharmaceutically-acceptable salt of a compound of the FormulaI is, for example, an acid-addition salt of a compound of the Formula Iwhich is sufficiently basic, for example an acid-addition salt with aninorganic or organic acid such as hydrochloric, hydrobromic, sulphuric,trifluoroacetic, citric or maleic acid; or, for example a salt of acompound of the Formula I which is sufficiently acidic, for example analkali or alkaline earth metal salt such as a calcium or magnesium salt,or an ammonium salt, or a salt with an organic base such as methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Various forms of prodrugs are known in the art. For examples of suchprodrug derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285(1988); and

e) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984).

Examples of such pro-drugs may be used to form in-vivo-cleavable estersof a compound of the Formula I. An in-vivo-cleavable ester of a compoundof the Formula I containing a carboxy group is, for example, apharmaceutically-acceptable ester which is cleaved in the human oranimal body to produce the parent acid. Suitablepharmaceutically-acceptable esters for carboxy include(1-6C)alkoxymethyl esters, for example methoxymethyl;(1-6C)alkanoyloxymethyl esters, for example pivaloyloxymethyl;phthalidyl esters; (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters, forexample 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters,for example 5-methyl-1,3-dioxolan-2-ylmethyl; and(1-6C)alkoxycarbonyloxyethyl esters, for example1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in thecompounds of this invention.

Particular novel compounds of the first aspect of the invention include,for example, amide derivatives of the Formula I, orpharmaceutically-acceptable salts thereof, wherein:

(a) R³ is hydrogen, halogeno (such as fluoro, chloro or bromo) or(1-6C)alkyl (such as methyl, ethyl, propyl and isopropyl), preferably R³is hydrogen, chloro, methyl or ethyl, more preferably hydrogen, chloroor methyl; and X, Y, R¹, R², Q, m, n and q have any of the meaningsdefined hereinbefore or in this section relating to particular novelcompounds of the invention;

(b) Q is phenyl or a heteroaromatic 5- or 6-membered monocyclic ring ora 9- or 10-membered bicyclic ring with up to five ring heteroatomsselected from oxygen, nitrogen and sulphur which bears a basicsubstituent selected from the substituents for Q defined hereinbefore;and X, Y, R¹, R², R³, m, n and q have any of the meanings definedhereinbefore or in this section relating to particular novel compoundsof the invention;

(c) Q is phenyl, indenyl, indanyl or fluorenyl which optionally bears 1,2 or 3 substituents selected from the substituents for Q definedhereinbefore; and X, Y, R¹, R², R³, m, n and q have any of the meaningsdefined hereinbefore or in this section relating to particular novelcompounds of the invention;

(d) Q is phenyl or a heteroaromatic 5- or 6-membered monocyclic ring ora 9- or 10-membered bicyclic ring with up to five ring heteroatomsselected from oxygen, nitrogen and sulphur which bears a basicsubstituent selected from amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy,(1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino,di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkyl-amino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino,amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino,di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, heteroaryl,heteroaryl-(1-6C)alkyl, heteroaryl-(1-6C)alkoxy, heterocyclyl,heterocyclyl-(1-6C)alkyl and heterocyclyl-(1-6C)alkoxy, and wherein anyheteroaryl or heterocyclyl group in a basic substituent on Q mayoptionally bear 1 or 2 substituents selected from halogeno, (1-6C)alkyl,(2-6C)alkanoyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; andX, Y, R¹, R², R³, m, n and q have any of the meanings definedhereinbefore or in this section relating to particular novel compoundsof the invention;

(e) Q is phenyl or a heteroaromatic 5- or 6-membered monocyclic ring ora 9- or 10-membered bicyclic ring with up to five ring heteroatomsselected from oxygen, nitrogen and sulphur which optionally bears 1, 2or 3 substituents selected from hydroxy, halogeno, trifluoromethyl,cyano, nitro, amino, carboxy, (1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,(2-6C)alkanoyl, halogeno-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, halogeno-(2-6C)alkoxy,hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy,carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy,amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy,di-[(1-6C)alkyl]amino-(2-6C)alkoxy, pyridyl, imidazolyl,pyridyl-(1-6C)alkyl, imidazolyl-(1-6C)alkyl, pyridyl-(1-6C)alkoxy,imidazolyl-(1-6C)alkoxy, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, 4-(1-6C)alkylpiperazinyl, 4-(2-6C)alkanoylpiperazinyl,pyrrolidinyl-(1-6C)alkyl, piperidinyl-(1-6C)alkyl,morpholinyl-(1-6C)alkyl, piperazinyl-(1-6C)alkyl,4-(1-6C)alkylpiperazinyl-(1-6C)alkyl,4-(2-6C)alkanoylpiperazinyl-(1-6C)alkyl, pyrrolidinyloxy,piperidinyloxy, 1-(1-6C)alkylpiperidinyloxy, pyrrolidinyl-(2-6C)alkoxy,piperidinyl-(2-6C)alkoxy, morpholinyl-(2-6C)alkoxy,piperazinyl-(2-6C)alkoxy, 4-(1-6C)alkylpiperazinyl-(2-6C)alkoxy and4-(2-6C)alkanoylpiperazinyl-(2-6C)alkoxy or Q bears a(1-3C)alkylenedioxy substituent; and X, Y, R¹, R², R³, m, n and q haveany of the meanings defined hereinbefore or in this section relating toparticular novel compounds of the invention;

(f) Q is phenyl, indenyl, indanyl, fluorenyl or a heteroaromatic 5- or6-membered monocyclic ring with up to three ring heteroatoms selectedfrom oxygen, nitrogen and sulphur which optionally bears 1, 2 or 3substituents selected from hydroxy, halogeno, trifluoromethyl, cyano,nitro, amino, carboxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, (2-6C)alkanoyl,(1-6C)alkanoylamino, (1-6C)alkanesulphonylamino,N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, phenyl, furyl, thienyl,azetidinyl, pyrrolinyl, pyrrolidinyl, 1,1-dioxidoisothiazolidinyl,piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, homopiperazinyl,pyrrolidinyl-(1-6C)alkyl, piperidinyl-(1-6C)alkyl,morpholinyl-(1-6C)alkyl and piperazinyl-(1-6C)alkyl, and wherein anyphenyl, furyl, thienyl or heterocyclyl group in a substituent on Q mayoptionally bear 1 or 2 substituents selected from halogeno, (1-6C)alkyl,(1-6C)alkoxy and (2-6C)alkanoyl; and X, Y, R¹, R², R³, m, n and q haveany of the meanings defined hereinbefore or in this section relating toparticular novel compounds of the invention;

(g) Q is phenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl,benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl whichoptionally bears 1 or 2 substituents selected from those defined inparagraph (b), (d) or (e) hereinbefore; and X, Y, R¹, R², R³, m, n and qhave any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention;

(h) Q is phenyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-oxazolyl,3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3- or 4-pyrazolyl, 2-,4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 3- or4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 2-, 3-, 5- or6-benzofuranyl, 2-, 3-, 5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl,2-, 5- or 6-benzoxazolyl, 2-, 5, - or 6-benzimidazolyl, 2-, 5- or6-benzothiazolyl, 3-, 5- or 6-indazolyl, 5-benzofurazanyl, 2-, 3-, 6- or7-quinolyl, 3-, 6- or 7-isoquinolyl, 2-, 6- or 7-quinazolinyl, 2-, 6- or7-quinoxalinyl, or 1,8-naphthyridinyl-2-yl or 1,8-naphthyridinyl-3-ylwhich optionally bears 1 or 2 substituents selected from those definedin paragraph (b), (d) or (e) hereinbefore; and X, Y, R¹, R², R³, m, nand q have any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention;

(i) Q is a heteroaromatic 5- or 6-membered monocyclic ring, a 9- or10-membered bicyclic ring or a 13- or 14-membered tricyclic ring eachwith up to five ring heteroatoms selected from oxygen, nitrogen andsulphur which optionally bears 1, 2 or 3 substituents selected fromhydroxy, halogeno, trifluoromethyl, cyano, nitro, amino, carboxy,(1-6C)alkyl, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl; and X, Y, R¹, R², R³, m,n and q have any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention;

(j) Q is a heteroaromatic 13- or 14-membered tricyclic ring each with upto five ring heteroatoms selected from oxygen, nitrogen and sulphurwhich optionally bears 1, 2 or 3 substituents selected from hydroxy,halogeno, trifluoromethyl, cyano, nitro, amino, carboxy, (1-6C)alkyl,(1-6C)alkoxy, (1-3 C)alkylenedioxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl; and X, Y, R¹, R², R³, mn and q have any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention;

(k) Q is furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl,benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, dibenzofuranyl,dibenzothiophenyl or xanthenyl which optionally bears 1 or 2substituents selected from those defined in paragraph (i) hereinbefore;and X, Y, R¹, R², R³, m, n and q have any of the meanings definedhereinbefore or in this section relating to particular novel compoundsof the invention,

(l) Q is 1-, 2- or 3-carbazolyl, 1-, 2-, 3- or 4-dibenzofuranyl or 1-,2-, 3- or 4-dibenzothiophenyl which optionally bears 1 or 2 substituentsselected from those defined in paragraph (i) hereinbefore; and X, Y, R¹,R², R³, m, n and q have any of the meanings defined hereinbefore or inthis section relating to particular novel compounds of the invention;

(m) n is 0; and X, Y, R¹, R³, Q, m and q have any of the meaningsdefined hereinbefore or in this section relating to particular novelcompounds of the invention;

(n) n is 1 and R² is halogeno or (1-6C)alkyl; and X, Y, R¹, R³, Q, m andq have any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention;

(o) q is 0, and X, Y, R¹, R², R³, Q, m and n have any of the meaningsdefined hereinbefore or in this section relating to particular novelcompounds of the invention;

(p) m is 1 and R¹ is amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy,(1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino,di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkyl-amino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, heteroaryl,heteroaryl-(1-6C)alkyl, heteroaryl-(1-6C)alkoxy, heterocyclyl,heterocyclyl-(1-6C)alkyl, heterocyclyloxy or heterocyclyl-(1-6C)alkoxy,and wherein any heteroaryl or heterocyclyl group in a R¹ substituent mayoptionally bear 1 or 2 substituents selected from hydroxy, halogeno,(1-6C)alkyl, (1-6C)alkoxy, (2-6C)alkanoyl, amino, (1-6C)alkylamino anddi-[(1-6C)alkyl]amino; and X, Y, R², R³, Q, n and q have any of themeanings defined hereinbefore or in this section relating to particularnovel compounds of the invention;

(q) m is 1 and R¹ is amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy,(1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino,di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkyl-amino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, pyridyl,imidazolyl, pyridyl-(1-6C)alkyl, imidazolyl-(1-6C)alkyl,pyridyl-(1-6C)alkoxy, imidazolyl-(1-6C)alkoxy, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, 4-(1-6C)alkylpiperazinyl,homopiperazinyl, 4-(1-6C)alkylhomopiperazinyl,4-(2-6C)alkanoylpiperazinyl, pyrrolidinyl-(1-6C)alkyl,piperidinyl-(1-6C)alkyl, morpholinyl-(1-6C)alkyl,piperazinyl-(1-6C)alkyl, 4-(1-6C)alkylpiperazinyl-(1-6C)alkyl,4-(2-6C)alkanoylpiperazinyl-(1-6C)alkyl, pyrrolidinyloxy,piperidinyloxy, 1-(1-6C)alkylpiperidinyloxy, pyrrolidinyl-(2-6C)alkoxy,piperidinyl-(2-6C)alkoxy, morpholinyl-(2-6C)alkoxy,piperazinyl-(2-6C)alkoxy, 4-(1-6C)alkylpiperazinyl-(2-6C)alkoxy or4-(2-6C)alkanoylpiperazinyl-(2-6C)alkoxy; and X, Y, R², R³, Q, n and qhave any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention;

(r) m is 1 and R¹ is hydroxy, halogeno, trifluoromethyl, cyano,mercapto, nitro, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl or(1-6C)alkoxy; and X, Y, R², R³, Q, n and q have any of the meaningsdefined hereinbefore or in this section relating to particular novelcompounds of the invention;

(s) m is 2 and the first R¹ substituent is selected from thesubstituents specified in paragraph (q) hereinbefore and the second R¹substituent is selected from the substituents specified in paragraph (r)hereinbefore; and X, Y, R², R³, Q, n and q have any of the meaningsdefined hereinbefore or in this section relating to particular novelcompounds of the invention;

(t) each of X and Y is a CH group; and R¹, R², R³, Q, m, n and q haveany of the meanings defined hereinbefore or in this section relating toparticular novel compounds of the invention; and

(u) one or both of X and Y is a N group; and R¹, R², R³, Q, m, n and qhave any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention.

Particular novel compounds of the second aspect of the inventioninclude, for example, amide derivatives of the Formula I, orpharmaceutically-acceptable salts thereof. wherein:

(a) R³ is halogeno (such as fluoro, chloro or bromo) or (1-6C)alkyl(such as methyl, ethyl, propyl and isopropyl), preferably R³ is chloro,methyl or ethyl, more preferably chloro or methyl; and X, Y, R¹, R², Q,m, n and q have any of the meanings defined hereinbefore.

A preferred compound of the first aspect of the invention is an amidederivative of the Formula I wherein X is CH or N:

Y is CH or N;

R³ is hydrogen, fluoro, chloro, bromo, methyl or ethyl;

m is 0, 1 or 2;

R¹ is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl,ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl,dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy,2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy,3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino,3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl,pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,4-methylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl,4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl,morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl,4-acetylpiperazinylmethyl, pyrrolidinyloxy, 1-methylpyrrolidinyloxy,piperidinyloxy, 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy,3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy,2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy,3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy,3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy or3-(4-acetylpiperazinyl)propoxy;

n is 0 or 1;

R² is fluoro, chloro, bromo, methyl or ethyl;

q is 0; and

Q is phenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl,benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl whichoptionally bears 1 or 2 substituents selected from hydroxy, fluoro,chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy,methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino,aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy,3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy,3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl,4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl,piperidinylmethyl, morpholinylmethyl, piperazinylmethyl,4-methylpiperazinylmethyl, 4-acetylpiperazinylmethyl, pyrrolidinyloxy,1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy,2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy,3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy,2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy,2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy,2-(4-acetylpiperazinyl)ethoxy and 3-(4-acetylpiperazinyl)propoxy; or apharmaceutically-acceptable salt thereof.

A further preferred compound of the first aspect of the invention is anamide derivative of the Formula I wherein

X is CH;

Y is CH or N;

R³ is hydrogen, chloro or methyl;

m is 0, 1 or 2;

R¹ is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano methyl,ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl,dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy,2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy,3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino,3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethoxy, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy,3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or3-(4-acetylpiperazin-1-yl)propoxy;

n is 0;

q is 0; and

Q is phenyl, 2-furyl, 2-thienyl, 4-oxazolyl, 5-isoxazolyl, 4-thiazolyl,5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-benzofuranyl,2-indolyl, 2-benzothienyl, 2-benzoxazolyl, 2-benzimidazolyl,2-benzothiazolyl, 4-benzofurazanyl, 2-quinolyl, 6-quinolyl, 7-quinolyl,3-isoquinolyl, 6-quinazolinyl, 7-quinazolinyl, 6-quinoxalinyl or7-quinoxalinyl which optionally bears 1 or 2 substituents selected fromhydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl,methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino,diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl,dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy,3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy,3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and3-(4-acetylpiperazin-1-yl)propoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the first aspect of the invention is anamide derivative of the Formula I wherein X is CH;

Y is CH or N;

R³ is hydrogen, chloro or methyl;

m is 0, 1 or 2;

R¹ is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl,ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl,dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy,2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy,3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino,3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy,3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or3-(4-acetylpiperazin-1-yl)propoxy;

n is 0;

q is 0; and

Q is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl which optionally bears 1or 2 substituents selected from hydroxy, fluoro, chloro,trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy,methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino,aminomethyl, methyl aminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy,3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy,3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl,4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy,pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl,4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl,morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and3-(4-acetylpiperazin-1-yl)propoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the first aspect of the invention is anamide derivative of the Formula I wherein X is CH;

Y is CH or N;

R³ is hydrogen, chloro or methyl;

m is 1 or 2;

R¹ is hydroxy, fluoro, chloro, methyl, ethyl, propyl, methoxy,dimethylaminomethyl diethylaminomethyl, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,3-dimethylamino-2-hydroxypropoxy, 3-diethylamino-2-hydroxypropoxy,2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino,3-methylaminopropylamino, 2-dimethylaminoethylamino,2-diethylaminoethylamino, 3-dimethylaminopropylamino,4-dimethylaminobutylamino, 3-amino-2-hydroxypropylamino,3-dimethylamino-2-hydroxypropylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino,piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,4-(2-hydroxyethyl)piperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 1-benzylpiperidin-4-yloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-hydroxy-3-pyrrolidin-1-ylpropoxy, 2-hydroxy-3-piperidinopropoxy,2-hydroxy-3-morpholinopropoxy, piperidin-4-ylamino,1-methylpiperidin-4-ylamino, 1-benzylpiperidin-4-ylamino,2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1ylpropylamino,2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino,3-piperidinopropylamino, 2-piperazin-1-ylethylamino,3-piperazin-1-ylpropylamino, 2-(4-methylpiperazin-1-yl)ethylamino,3-(4-methylpiperazin-1-yl)propylamino,2-(1-methylpyrrolidin-2-yl)ethylamino,3-(1-methylpyrrolidin-2-yl)propylamino, 2-dimethylaminoethylaminomethyl,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl,3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl or 2-pyridylmethoxy;

n is 0;

q is 0; and

Q is 2-pyridyl, 3-pyridyl or 4-pyridyl which bears a substituentselected from pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,2-hydroxymethylpyrrolidin-1-yl, morpholino, piperidino,4-hydroxypiperidin-1-yl, piperazin-1-yl and 4-methylpiperazin-1-yl;

or a pharmaceutically-acceptable salt thereof.

An especially preferred compound of the first aspect of the invention isan amide derivative of the Formula I wherein X is CH;

Y is CH or N;

R³ is hydrogen, chloro or methyl;

m is 1 and R¹ is selected from diethylaminomethyl,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino,piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,2-piperidinoethoxy, 2-morpholinoethoxy,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl,3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2-pyridylmethoxy;

n is 0;

q is 0; and

Q is 3-pyridyl or 4-pyridyl which bears a substituent selected frompyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and4-methylpiperazin-1-yl;

or a pharmaceutically-acceptable salt thereof.

A further especially preferred compound of the first aspect of theinvention is an amide derivative of the Formula I wherein X is CH;

Y is CH or N;

R³ is hydrogen, chloro or methyl;

m is 1 and R¹ is N-(3-dimethylaminopropyl)-N-methylamino,4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,4-methylpiperazin-1-ylmethyl or pyrrolidin-3-yloxy;

n is 0;

q is 0; and

Q is 2-morpholinopyrid-4-yl;

or a pharmaceutically-acceptable salt thereof.

A particular preferred compound of the invention is, for example:

N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamide,

N-[6-(4-ethylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamide,

N-[6-(4-methylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamideor

N-{6-[N-(3-dimethylaminopropyl)-N-methylamino]pyrid-3-yl}-2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamide;

or a pharmaceutically-acceptable salt thereof.

A preferred compound of the second aspect of the invention is an amidederivative of the Formula I wherein X is CH or N;

Y is CH or N;

R³ is fluoro, chloro, bromo, methyl or ethyl;

m is 0, 1 or 2;

R¹ is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl,ethyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino,diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyldiethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino,2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl,pyridylmethoxy, 3-pyrrolinyl, pyrrolidinyl, piperidinyl,homopiperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl,4-ethylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl,4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl,morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl,homopiperazinylmethyl, 4-methylhomopiperazinylmethyl,4-acetylpiperazinylmethyl, pyrrolidinyloxy, 1-methylpyrrolidinyloxy,piperidinyloxy, 1-methylpiperidinyloxy, homopiperidinyloxy,1-methylhomopiperidinyloxy, 2-(pyrrolidinyl)ethoxy,3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy,2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy,3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy,3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy,3-(4-acetylpiperazinyl)propoxy, 3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidinylethyl)aminomethyl,3-pyrrolidinylpropylaminomethyl, 2-morpholinylethylaminomethyl,3-morpholinylpropylaminomethyl, 2-piperazinylethylaminomethyl,3-(4-methylpiperazinylpropyl)aminomethyl, pyridylmethoxy,imidazolylmethoxy, thiazolylmethoxy and 2-methylthiazolylmethoxy;

n is 0 or 1;

R² is fluoro, chloro, bromo, methyl or ethyl;

q is 0; and

Q is phenyl, indenyl, indanyl, tetrahydronaphthyl, fluorenyl, furyl,thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl,benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, dibenzofuranyl,dibenzothiophenyl or xanthenyl which optionally bears 1 or 2substituents selected from hydroxy, fluoro, chloro, trifluoromethyl,cyano, amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy,cyclopentyloxy, methylenedioxy, methylamino, ethylamino, dimethylamino,diethylamino, acetamido, propionamido, methanesulphonamido,N-methylmethanesulphonamido, aminomethyl, methylaminomethyl,ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl,2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy,3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy,2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy,3-ethylaminopropoxy, 2-dimethylaminoethoxy 2-diethylaminoethoxy,3-dimethylaminopropoxy, 3-diethylaminopropoxy, phenyl, furyl, thienyl,pyridyl, pyridylimethyl, pyridylmethoxy, azetidinyl, 3-pyrrolinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl,4-methylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl,4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl,morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl,4-acetylpiperazinylmethyl, pyrrolidinyloxy, 1-methylpyrrolidinyloxy,piperidinyloxy, 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy,3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy,2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy,3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy,3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy and3-(4-acetylpiperazinyl)propoxy, and wherein any phenyl, furyl, thienyl,pyridyl or heterocyclyl group in a substituent on Q may optionally bear1 or 2 substituents selected from fluoro, chloro, methyl and methoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the second aspect of the invention is anamide derivative of the Formula I wherein

X is CH;

Y is CH or N;

R³ is chloro or methyl;

m is 0, 1 or 2;

R¹ is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl,ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl,dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy,2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy,3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino,3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy,3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or3-(4-acetylpiperazin-1-yl)propoxy;

n is 0;

q is 0; and

Q is phenyl, 2-furyl, 2-thienyl, 4-oxazolyl, 5-isoxazolyl 4-thiazolyl,5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-benzofuranyl,2-indolyl, 2-benzothienyl, 2-benzoxazolyl, 2-benzimidazolyl,2-benzothiazolyl, 4-benzofurazanyl, 2-quinolyl, 6-quinolyl, 7-quinolyl,3-isoquinolyl, 6-quinazolinyl, 7-quinazolinyl, 6-quinoxalinyl or7-quinoxalinyl which optionally bears 1 or 2 substituents selected fromhydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl,methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino,diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl,dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy,3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy,3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and3-(4-acetylpiperazin-1-yl)propoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the second aspect of the invention is anamide derivative of the Formula I wherein X is CH;

Y is CH or N;

R³ is chloro or methyl;

m is 0, 1 or 2;

R¹ is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl,ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl,dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy,2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy,3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino,3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy,3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or3-(4-acetylpiperazin-1-yl)propoxy;

n is 0;

q is 0; and

Q is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl which optionally bears 1or 2 substituents selected from hydroxy, fluoro, chloro,trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy,methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino,aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy,3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy,3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl,4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy,pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl,4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl,morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and3-(4-acetylpiperazin-1-yl)propoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the second aspect of the invention is anamide derivative of the Formula I wherein X is CH;

Y is CH or N;

R³ is chloro or methyl;

m is 1 or 2;

R¹ is hydroxy, fluoro, chloro, methyl, ethyl, propyl, methoxy,dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,3-dimethylamino-2-hydroxypropoxy, 3-diethylamino-2-hydroxypropoxy,2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino,3-methylaminopropylamino, 2-dimethylaminoethylamino,2-diethylaminoethylamino, 3-dimethylaminopropylamino,4-dimethylaminobutylamino, 3-amino-2-hydroxypropylamino,3-dimethylamino-2-hydroxypropylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino,piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,4-(2-hydroxyethyl)piperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 1-benzylpiperidin-4-yloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-hydroxy-1-pyrrolidin-1-ylpropoxy, 2-hydroxy-3-piperidinopropoxy,2-hydroxy-3-morpholinopropoxy, piperidin-4-ylamino,1-methylpiperidin-4-ylamino, 1-benzylpiperidin-4-ylamino,2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1-ylpropylamino,2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino,3-piperidinopropylamino, 2-piperazin-1-ylethylamino,3-piperazin-1-ylpropylamino, 2-(4-methylpiperazin-1-yl)ethylamino,3-(4-methylpiperazin-1-yl)propylamino,2-(1-methylpyrrolidin-2-yl)ethylamino,3-(1-methylpyrrolidin-2-yl)propylamino, 2-dimethylaminoethylaminomethyl,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl,3-morpholinylpropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl or 2-pyridylmethoxy;

n is 0;

q is 0; and

Q is 2-pyridyl, 3-pyridyl or 4-pyridyl which bears a substituentselected from pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,2-hydroxymethylpyrrolidin-1-yl, morpholino, piperidino,4-hydroxypiperidin-1-yl, piperazin-1-yl and 4-methylpiperazin-1-yl;

or a pharmaceutically-acceptable salt thereof.

An especially preferred compound of the second aspect of the inventionis an amide derivative of the Formula I wherein X is CH;

Y is CH or N;

R³ is chloro or methyl;

m is 1 and R¹ is selected from diethylaminomethyl,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino,piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, homopiperazin-1-yl 4-methylhomopiperazin-1-yl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,2-piperidinoethoxy, 2-morpholinoethoxy,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl,3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2-pyridylmethoxy;

n is 0;

q is 0; and

Q is 3-pyridyl or 4-pyridyl which bears a substituent selected frompyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and4-methylpiperazin-1-yl;

or a pharmaceutically-acceptable salt thereof.

A further especially preferred compound of the second aspect of theinvention is an amide derivative of the Formula I wherein X is CH;

Y is CH or N;

R³ is chloro or methyl;

m is 1 and R¹ is selected from diethylaminomethyl,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, 3-pyrrolin-1-yl,pyrrolidin-1-yl, morpholino, piperidino, homopiperidin-1-yl,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl,homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,N-methylpiperidin-4-yloxy, homopiperidin-4-yloxy,N-methylhomopiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,2-piperidinoethoxy, 2-morpholinoethoxy,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl 2-morpholinoethylaminomethyl,3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl, 2-pyridylmethoxy,4-thiazolylmethoxy and 2-methylthiazol-4-ylmethoxy;

n is 0;

q is 0; and

Q is phenyl which bears 1 or 2 substituents selected from fluoro,chloro, trifluoromethyl, methoxy, cyclopentyloxy, acetamido,N-methylmethanesulphonamido, 2-furyl, azetidin-1-yl, 3-pyrrolin-1-yl,pyrrolidin-1-yl, morpholino, piperidino, homopiperidino, piperazin-1-yl,homopiperazin-1-yl, 4-methylpiperazin-1-yl and4-methylhomopiperazin-1-yl, or Q is 1-fluorenyl or 4-dibenzofuranyl, orQ is 3-pyridyl or 4-pyridyl which bears a substituent selected fromazetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino,homopiperidino, piperazin-1-yl, homopiperazin-1-yl,4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl;

or a pharmaceutically-acceptable salt thereof.

A further especially preferred compound of the second aspect of theinvention is an amide derivative of the Formula I wherein X is CH;

Y is CH or N;

R³ is chloro or methyl;

m is 1 and R¹ is N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or4-methylpiperazin-1-ylmethyl;

n is 0;

q is 0; and

Q is 2-(pyrrolidin-1-yl)pyrid-4-yl, 2-(3-pyrrolin-1-yl)pyrid-4-yl,2-piperidinopyrid-4-yl, 2-morpholinopyrid-4-yl, 1-fluorenyl,dibenzofuran-4-yl, 3-acetamidophenyl or 3-(2-furyl)phenyl;

or a pharmaceutically-acceptable salt thereof.

A further especially preferred compound of the second aspect of theinvention is an amide derivative of the Formula I wherein X is Ch;

Y is CH or N;

R³ is chloro or methyl;

m is 1 and R¹ is N-(3-dimethylaminopropyl)-N-methylamino,4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or4-methylpiperazin-1-ylmethyl;

n is 0;

q is 0; and

Q is 2-morpholinopyrid-4-yl;

or a pharmaceutically-acceptable salt thereof.

An amide derivative of the Formula I, or a pharmaceutically-acceptablesalt or in-vivo-cleavable ester thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare a novel amide derivativeof the Formula I are provided as a further feature of the invention andare illustrated by the following representative process variants inwhich, unless otherwise stated, X, Y, R¹, R², R³, m, n, q and Q have anyof the meanings defined hereinbefore. Necessary starting materials maybe obtained by standard procedures of organic chemistry. The preparationof such starting materials is described in conjunction with thefollowing representative process variants and within the accompanyingExamples. Alternatively necessary starting materials are obtainable byanalogous procedures to those illustrated which are within the ordinaryskill of an organic chemist.

(a) A compound of the Formula I, or a pharmaceutically-acceptable saltor in-vivo-cleavable ester thereof, may be prepared by reacting ananiline of the Formula II

with a benzoic acid of the Formula III, or an activated derivativethereof,

under standard amide bond forming conditions, wherein variable groupsare as defined hereinbefore and wherein any functional group isprotected, if necessary, and:

(i) removing any protecting groups;

(ii) optionally forming a pharmaceutically-acceptable salt orin-vivo-cleavable ester.

A suitable reactive derivative of a carboxylic acid of the Formula IIIis, for example, an acyl halide, for example an acyl chloride formed bythe reaction of the acid and an inorganic acid chloride, for examplethionyl chloride; a mixed anhydride, for example an anhydride formed bythe reaction of the acid and a chloroformate such as isobutylchloroformate; an active ester, for example an ester formed by thereaction of the acid with a phenol such as pentafluorophenol, with anester such as pentafluorophenyl trifluoroacetate or with an alcohol suchas N-hydroxybenzotriazole; an acyl azide, for example an azide formed bythe reaction of the acid and an azide such as diphenylphosphoryl azide;an acyl cyanide, for example a cyanide formed by the reaction of an acidand a cyanide such as diethylphosphoryl cyanide; or the product of thereaction of the acid and a carbodiimide such asdicyclohexylcarbodiimide.

The standard amide bond forming conditions conveniently include thepresence of a suitable base such as, for example, an alkali or alkalineearth metal carbonate, alkoxide, hydroxide or hydride, for examplesodium carbonate, potassium carbonate, sodium ethoxide, potassiumbutoxide, sodium hydroxide, potassium hydroxide, sodium hydride orpotassium hydride, or an organometallic base such as an alkyl-lithium,for example n-butyl-lithium, or a dialkylamino-lithium, for examplelithium di-isopropylamide, or, for example, an organic amine base suchas, for example, pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, morpholine ordiazabicyclo[5.4.0]undec-7-ene.

The reaction is also preferably carried out in a suitable inert solventor diluent, for example methanol, ethanol, tetrahydrofuran, methylenechloride, 1,2-dimethoxyethane, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide oracetone, and at a temperature in the range, for example, 0 to 100° C.conveniently at or near ambient temperature.

Typically a carbodiimide coupling reagent is used in the presence of anorganic solvent (preferably an anhydrous polar aprotic organic solvent)at a non-extreme temperature, for example in the region −10 to 40° C.,typically at ambient temperature of about 20° C.

Typical standard amide bond forming conditions include activating thecarboxy group for example by treatment with a halo reagent (for exampleoxalyl chloride) to form an acyl halide in an organic solvent at ambienttemperature and then reacting the activated compound with an aniline.Any functional groups are protected and deprotected as necessary.Conveniently a carbodiimide coupling reagent is used in the presence ofan organic solvent (preferably an anhydrous polar aprotic organicsolvent) at a non-extreme temperature, for example in the region −10 to40° C., typically at ambient temperature of about 20° C.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1-4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned is of course within the scope of the invention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (for example isopropyl, tert-butyl); lower alkoxylower alkyl groups (for example methoxymethyl, ethoxymethyl,isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (forexample acetoxymethyl, propionyloxymethyl, butyryloxymethyl,pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (forexample 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl), aryl loweralkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups(for example trimethylsilyl and tert-butyldimethylsilyl); tri(loweralkyl)silyl lower alkyl groups (for example trimethylsilylethyl); and(2-6C)alkenyl groups (for example allyl and vinylethyl). Methodsparticularly appropriate for the removal of carboxyl protecting groupsinclude for example acid-, base-, metal- or enzymically-catalysedhydrolysis.

Examples of hydroxy protecting groups include lower alkyl groups (forexample tert-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkylsilyl (for example trimethylsilyl, tert-butyldimethylsilyl) andaryl lower alkyl (for example benzyl) groups.

Examples of amino protecting groups include formyl, aralkyl groups (forexample benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl andfurylmethyl groups; lower alkoxycarbonyl (for exampletert-butoxycarbonyl); lower alkenyloxycarbonyl (for exampleallyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl andtert-butyldimethylsilyl); alkylidene (for example methylidene);benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis for groups such as p-nitrobenzyloxycarbonyl, hydrogenationfor groups such as benzyl and photolytically for groups such aso-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry 4th Edition, byJerry March, published by John Wiley & Sons 1992, for general guidanceon reaction conditions and reagents. The reader is referred toProtective Groups in Organic Synthesis. 2nd Edition, by Green et al.,published by John Wiley & Sons for general guidance on protectinggroups.

The benzoic acid of the Formula III may be prepared by the cleavage ofthe corresponding ester thereof which, in turn, may be prepared by thereaction of an aniline of the Formula IV

wherein R is, for example, lower alkyl or benzyl with a carboxylic acidof the Formula V, or an activated derivative thereof as definedhereinbefore,

under standard amide bond forming conditions as defined hereinbefore,wherein variable groups are as defined hereinbefore and wherein anyfunctional group is protected if necessary.

(b) A compound of the Formula I, or a pharmaceutically-acceptable saltor in-vivo-cleavable ester thereof, may be prepared by reacting ananiline of the Formula VI

with a carboxylic acid of the Formula V, or a reactive derivativethereof as defined hereinbefore,

under standard amide bond forming conditions as defined hereinbefore,wherein variable groups are as defined hereinbefore and wherein anyfunctional group is protected if necessary, and;

(i) removing any protecting groups; and

(ii) optionally forming a pharmaceutically-acceptable salt orin-vivo-cleavable ester.

The aniline of the Formula VI may be prepared by the reduction of thecorresponding nitrobenzene compound of the Formula VII

wherein variable groups are as defined hereinbefore and wherein anyfunctional group is protected if necessary.

Typical reaction conditions for the reduction include the use ofammonium formate or hydrogen gas in the presence of a catalyst forexample a metallic catalyst such as palladium-on-carbon. Alternatively adissolving metal reduction may be carried out, for example using iron inthe presence of an acid, for example an inorganic or organic acid suchas hydrochloric, hydrobromic, sulphuric or acetic acid. The reaction isconveniently carried out in the presence of an organic solvent(preferably a polar protic solvent) and preferably with heating, forexample to about 60° C. Any functional groups are protected anddeprotected as necessary.

The nitrobenzene compound of the Formula VII may be prepared by thereaction of the aniline of the Formula II

with a carboxylic acid of the Formula VIII, or a reactive derivativethereof as defined hereinbefore,

under standard amide bond forming conditions as defined hereinbefore,wherein variable groups are as defined hereinbefore and wherein anyfunctional group is protected if necessary.

(c) A compound of the Formula I wherein R¹ or a substituent on Q is(1-6C)alkoxy or substituted (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylamino, di-[(1-6C)alkyl]amino or substituted (1-6C)alkylaminomay be prepared by the alkylation, conveniently in the presence of asuitable base as defined hereinbefore, of an amide derivative of theFormula I wherein R¹ or a substituent on Q is hydroxy, mercapto or aminoas appropriate.

The reaction is preferably carried out in the presence of a suitableinert solvent or diluent, for example a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or adipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.The reaction is conveniently carried out at a temperature in the range,for example, 10 to 150° C., preferably in the range 20 to 80° C.

A suitable alkylating agent is, for example, any agent known in the artfor the alkylation of hydroxy to alkoxy or substituted alkoxy, or forthe alkylation of mercapto to alkylthio, or for the alkylation of aminoto alkylamino or substituted alkylamino, for example an alkyl orsubstituted alkyl halide, for example a (1-6C)alkyl chloride, bromide oriodide or a substituted (1-6C)alkyl chloride, bromide or iodide, in thepresence of a suitable base as defined hereinbefore, in a suitable inertsolvent or diluent as defined hereinbefore and at a temperature in therange, for example, 10 to 140° C. conveniently at or near ambienttemperature.

(d) A compound of the Formula I wherein a substituent on Q is amino,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, substituted (1-6C)alkylamino,substituted N-(1-6C)alkyl-(2-6C)alkylamino or a N-linked heterocyclylgroup may be prepared by the reaction, conveniently in the presence of asuitable base as defined hereinbefore, of an amide derivative of theFormula I wherein a substituent on Q is a suitable leaving group with anappropriate amine.

A suitable leaving group is, for example, a halogeno group such asfluoro, chloro or bromo, a (1-6C)alkanesulphonyloxy group such asmethanesulphonyloxy or an arylsulphonyloxy group such as4-toluenesulphonyloxy.

The reaction is conveniently carried out in the presence of a suitableinert diluent or carrier as defined hereinbefore and at a temperature inthe range, for example, 20 to 200° C. conveniently in the range 75 to150° C.

(e) A compound of the Formula I wherein R¹ or a substituent on Q is(1-6C)alkanoylamino or substituted (2-6C)alkanoylamino may be preparedby the acylation of a compound of the Formula I wherein R¹ or asubstituent on Q is amino.

A suitable acylating agent is, for example, any agent known in the artfor the acylation of amino to acylamino, for example an acyl halide, forexample a (1-6C)alkanoyl chloride or bromide, conveniently in thepresence of a suitable base, as defined hereinbefore, an alkanoic acidanhydride or mixed anhydride, for example a (1-6C)alkanoic acidanhydride such as acetic anhydride or the mixed anhydride formed by thereaction of an alkanoic acid and a (1-6C)alkoxycarbonyl halide, forexample a (1-6C)alkoxycarbonyl chloride, in the presence of a suitablebase as defined hereinbefore. In general the acylation is carried out ina suitable inert solvent or diluent as defined hereinbefore and at atemperature, in the range, for example, −30 to 120° C. conveniently ator near ambient temperature.

(f) A compound of the Formula I wherein R¹ or a substituent on Q is(1-6C)alkanesulphonylamino may be prepared by the reaction of a compoundof the Formula I wherein R¹ or a substituent on Q is amino with a(1-6C)alkanesulphonic acid, or an activated derivative thereof.

A suitable activated derivative of a (1-6C)alkanesulphonic acid is, forexample, an alkanesulphonyl halide, for example an alkanesulphonylchloride formed by the reaction of the sulphonic acid and an inorganicacid chloride, for example thionyl chloride. The reaction is preferablycarried out in the presence of a suitable base as defined hereinbefore,particularly pyridine, and in a suitable inert solvent or diluent asdefined hereinbefore, particularly methylene chloride.

(g) A compound of the Formula I wherein R¹ or a substituent on Q iscarboxy, carboxy-(1-6C)alkyl, carboxy-(1-6C)alkoxy,carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-carboxy-(1-6C)alkylamino orcarboxy-(2-6C)alkanoylamino may be prepared by the cleavage of acompound of the Formula I wherein R¹ or a substituent on Q is(1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl,(1-6C)alkoxycarbonyl-(1-6C)alkoxy,(1-6C)alkoxycarbonyl-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino or(1-6C)alkoxycarbonyl-(2-6C)alkanoylamino as appropriate.

The cleavage reaction may conveniently be carried out by any of the manyprocedures known in the art for such a transformation. The reaction maybe carried out, for example, by hydrolysis under acidic or basicconditions. A suitable base is, for example, an alkali metal, alkalineearth metal or ammonium carbonate or hydroxide for example sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide orammonium hydroxide. The reaction is preferably carried out in thepresence of water and a suitable solvent or diluent such as methanol orethanol. The reaction is conveniently carried out at a temperature inthe range 10 to 150° C., preferably at or near ambient temperature.

(h) A compound of the Formula I wherein R¹ is amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or aheterocyclyl-(1-6C)alkyl group may be prepared by the reaction,conveniently in the presence of a suitable base as defined hereinbefore,of a compound of the Formula IX

wherein X, Y, R², R³, n, q and Q have any of the meanings definedhereinbefore and Z is a suitable leaving group with an appropriate amineor heterocycle.

A suitable leaving group Z is, for example, a halogeno group such asfluoro, chloro or bromo, a (1-6C)alkanesulphonyloxy group such asmethanesulphonyloxy or an arylsulphonyloxy group such as4-toluenesulphonyloxy.

The reaction is conveniently carried out in the presence of a suitableinert diluent or carrier as defined hereinbefore and at a temperature inthe range, for example, 20 to 200° C., conveniently in the range 50 to150° C.

The following biological assays and Examples serve to illustrate thepresent invention.

Biological Assays

The following assays can be used to measure the p38 kinase-inhibitory,the TNF-inhibitory and anti-arthritic effects of the compounds of thepresent invention:

In vitro Enzyme Assay

The ability of compounds of the invention to inhibit the enzyme p38kinase was assessed. Activity of test compounds against each of the p38αand p38β isoforms of the enzyme was determined.

Human recombinant MKK6 (GenBank Accesion Number G1209672) was isolatedfrom Image clone 45578 (Genomics, 1996, 33, 151) and utilised to produceprotein in the form of a GST fusion protein in a pGEX vector usinganalogous procedures to those disclosed by J. Han et al., Journal ofBiological Chemistry, 1996, 271, 2886-2891. p38α (GenBank AccessionNumber G529039) and p38β (GenBank Accession Number G1469305) wereisolated by PCR amplification of human lymphoblastoid cDNA (GenBankAccession Number GM1416) and human foetal brain cDNA [synthesised frommRNA (Clontech. catalogue no. 6525-1) using a Gibco superscript cDNAsynthesis kit] respectively using oligonucleotides designed for the 5′and 3′ ends of the human p38α and p38β genes using analogous proceduresto those described by J. Han et al., Biochimica et Biophysica Acta.1995, 1265, 224-227 and Y. Jiang et al., Journal of BiologicalChemistry, 1996, 271, 17920-17926.

Both p38 protein isoforms were expressed in e coli in PET vectors. Humanrecombinant p38α and p38β isoforms were produced as 5′ c-myc, 6Histagged proteins. Both MKK6 and the p38 proteins were purified usingstandard protocols: the GST MKK6 was purified using a glutathionesepharose column and the p38 proteins were purified using nickel chelatecolumns.

The p38 enzymes were activated prior to use by incubation with MKK6 for3 hours at 30° C. The unactivated coli-expressed MKK6 retainedsufficient activity to fully activate both isoforms of p38. Theactivation incubate comprised p38α (10 μl of 10 mg/ml) or p38β (10 μl of5 mg/ml) together with MKK6 (10 μl of mg/ml), ‘Kinase buffer’ [100 μl;pH 7.4 buffer comprising Tris (50 mM). EGTA (0.1 mM), sodiumorthovanadate (0.1 mM) and β-mercaptoethanol (0.1%)] and MgATP (30 μl of50 mM Mg(OCOCH₃)₂ and 0.5 mM ATP). This produced enough activated p38enzyme for 3 Microtiter plates.

Test compounds were solubilised in DMSO and 10 μl of a 1:10 dilutedsample in ‘Kinase Buffer’ was added to a well in a Microtiter plate. Forsingle dose testing, the compounds were tested at 10 μM. ‘Kinase AssayMix’ [30 μl; comprising Myelin Basic Protein (Gibco BRL cat. no.1322B-010; 1 ml of a 3.33 mg/ml solution in water), activated p38 enzyme(50 μl) and ‘Kinase Buffer’ (2 ml)] was then added followed by ‘LabelledATP’ [10 μl; comprising 50 μM ATP, 0.1 μCi ³³P ATP (AmershamInternational cat. no. BF1000) and 50 mM Mg(OCOCH₃)₂]. The plates wereincubated at room temperature with gentle agitation. Plates containingp38α were incubated for 90 min and plates containing p38β were incubatedfor 45 min. Incubation was stopped by the addition of 50 μl of 20%trichloroacetic acid (TCA). The precipitated protein was phosphorylatedby p38 kinase and test compounds were assessed for their ability toinhibit this phosphorylation. The plates were filtered using a CanberraPackard Unifilter and washed with 2% TCA, dried overnight and counted ona Top Count scintillation counter.

Test compounds were tested initially at a single dose and activecompounds were retested to allow IC₅₀ values to be determined.

In vitro Cell-based Assays

(i) PBMC

The ability of compounds of this invention to inhibit TNFα productionwas assessed by using human peripheral blood mononuclear cells whichsynthesise and secrete TNFα when stimulated with lipopolysaccharide.

Peripheral blood mononuclear cells (PBMC) were isolated from heparinised(10 units/ml heparin) human blood by density centrifugation(Lymphoprep™; Nycomed). Mononuclear cells were resuspended in culturemedium [RPMI 1640 medium (Gibco) supplemented with 50 units/mlpenicillin, 50 μg/ml streptomycin, 2 mM glutamine and 1%heat-inactivated human AB serum (Sigma H-1513)]. Compounds weresolubilised in DMSO at a concentration of 50 mM, diluted 1:100 inculture medium and subsequently serial dilutions were made in culturemedium containing 1% DMSO. PBMCs (2.4×10⁵ cells in 160 μl culturemedium) were incubated with 20 μl of varying concentrations of testcompound (triplicate cultures) or 20 μl culture medium containing 1%DMSO (control wells) for 30 minutes at 37° C. in a humidified (5%CO₂/95%air) incubator (Falcon 3072; 96 well flat-bottom tissue culture plates).20 μl lipopolysaccharide [LPS E.Coli 0111:B4 (Sigma L-4130), finalconcentration 10 μg/ml] solubilised in culture medium was added toappropriate wells. 20 μl culture medium was added to “medium alone”control wells. Six “LPS alone” and four “medium alone” controls wereincluded on each 96 well plate. Varying concentrations of a known TNFαinhibitor were included in each test, i.e. an inhibitor of the PDE TypeIV enzyme (for example see Semmler, J. Wachtel. H and Endres, S., Int.J. Immunopharmac. (1993), 15(3), 409-413) or an inhibitor of pro TNFαconvertase (for example, see McGeehan, G. M. et al. Nature (1994) 370,558-561). Plates were incubated for 7 hours at 37° C. (humidifiedincubator) after which 100 μl of the supernatant was removed from eachwell and stored at −70° C. (96 well round-bottom plates; Corning 25850).TNFα levels were determined in each sample using a human TNFα ELISA (seeWO92/10190 and Current Protocols in Molecular Biology, vol 2 byFrederick M. Ausbel et al., John Wiley and Sons Inc.).${\% \quad {inhibition}} = {\frac{\begin{matrix}{\left( {{{LPS}\quad {alone}} - {{medium}\quad {alone}}} \right) -} \\\left( {{{test}\quad {concentration}} - {{medium}\quad {alone}}} \right)\end{matrix}}{\left( {{{LPS}\quad {alone}} - {{medium}\quad {alone}}} \right)} \times 100}$

(ii) Human Whole Blood

The ability of the compounds of this invention to inhibit TNFαproduction was also assessed in a human whole blood assay. Human wholeblood secretes TNFα when stimulated with LPS. This property of bloodforms the basis of an assay which is used as a secondary test forcompounds which profile as active in the PBMC test.

Heparinised (10 units/ml) human blood was obtained from volunteers. 160μl whole blood were added to 96 well round-bottom plates (Corning25850). Compounds were solubilised and serially diluted in RPMI 1640medium (Gibco) supplemented with 50 units/ml penicillin, 50 μg/mlstreptomycin and 2 mM glutamine, as detailed above. 20 μl of each testconcentration was added to appropriate wells (triplicate cultures). 20μl of RPMI 1640 medium supplemented with antibiotics and glutamine wasadded to control wells. Plates were incubated for 30 minutes at 37° C.(humidified incubator), prior to addition of 20 μl LPS (finalconcentration 10 μg/ml). RPMI 1640 medium was added to control wells.Six “LPS alone” and four “medium alone” controls were included on eachplate. A known TNFα synthesis/secretion inhibitor was included in eachtest. Plates were incubated for 6 hours at 37° C. (humidifiedincubator). Plates were centrifuged (2000 rpm for 10 minutes) and 100 μlplasma removed and stored at −70° C. (Corning 25850 plates). TNFα levelswere measured by ELISA (see WO92/10190 and Current Protocols inMolecular Biology, vol 2 by Frederick M. Ausbel et al., John Wiley andSons Inc.). The paired antibodies that were used in the ELIZA wereobtained from R&D Systems (catalogue nos. MAB610 anti-human TNFα coatingantibody, BAF210 biotinylated anti-human TNFα detect antibody).

Ex vivo/In vivo Assessment

The ability of the compounds of this invention as ex vivo TNFαinhibitors were assessed in the rat or mouse. Briefly, groups of maleWistar Alderley Park (AP) rats (180-210 g) were dosed with compound (6rats) or drug vehicle (10 rats) by the appropriate route, for exampleperoral (p.o.), intraperitoneal (i.p.) or subcutaneous (s.c.). Ninetyminutes later rats were sacrificed using a rising concentration of CO₂and bled out via the posterior vena cavae into 5 Units of sodiumheparin/ml blood. Blood samples were immediately placed on ice andcentrifuged at 2000 rpm for 10 min at 4° C. and the harvested plasmasfrozen at −20° C. for subsequent assay of their effect on TNFαproduction by LPS-stimulated human blood. The rat plasma samples werethawed and 175 μl of each sample was added to a set format pattern in a96 well round bottom plate (Corning 25850). 50 μl of heparinized humanblood was then added to each well, mixed and the plate was incubated for30 min at 37° C. (humidified incubator). LPS (25 μl; final concentration10 μg/ml) was added to the wells and incubation continued for a further5.5 hours. Control wells were incubated with 25 μl of medium alone.Plates were then centrifuged for 10 min at 2000 rpm and 200 μl of thesupernatants were transferred to a 96 well plate and frozen at −20° C.for subsequent analysis of TNF concentration by ELISA.

Data analysis by dedicated software calculates for each compound/dose:${\% \quad {inhibition}\quad {of}\quad {TNF}\quad \alpha} = {\frac{\begin{matrix}{{{Mean}\quad {TNF}\quad \alpha \quad ({Controls})} -} \\{{Mean}\quad {TNF}\quad \alpha \quad ({Treated})}\end{matrix}}{{Mean}\quad {TNF}\quad \alpha \quad ({Controls})} \times 100}$

Alternatively, mice could be used instead of rats in the aboveprocedure.

Test as Anti-arthritic Agent

Activity of a compound as an anti-arthritic agent was tested as follows.Acid soluble native type II collagen was shown by Trentham et al. [1] tobe arthritogenic in rats; it caused polyarthritis when administered inFreunds incomplete adjuvant. This is now known as collagen-inducedarthritis (CIA) and similar conditions can be induced in mice andprimates. Recent studies have shown that anti-TNF monoclonal antibodies[2] and TNF receptor-IgG fusion proteins [3] ameliorate established CIAindicating that TNF plays a key role in the pathophysioloy of CIA.Moreover, the remarkable efficacy reported for anti-TNF monoclonalantibodies in recent rheumatoid arthritis clinical trials indicates thatTNF plays a major role in this chronic inflammatory disease. Thus CIA inDBA/1 mice as described in references 2 and 3 is a tertiary model whichcan be used to demonstrate the anti-arthritic activity of a compound.Also see reference 4.

1. Trentham, D. E. et al., (1977) J. Exp. Med., 146, 857.

2. Williams, R. O. et al., (1992) Proc. Natl. Acad. Sci., 89, 9784.

3. Williams, R. O. et al., (1995) Immunology, 84, 433.

4. Badger, M. B. et al., (1996) The Journal of Pharmacology andExperimental Therapeutics, 279, 1453-1461.

Although the pharmacological properties of the compounds of the FormulaI vary with structural change as expected, in general a compound of theFormula I gives over 30% inhibition of p38α and/or p38β atconcentrations up to 10 μM. No physiologically unacceptable toxicity wasobserved at the effective dose for compounds tested of the presentinvention.

By way of example, the compoundN-{6-[N-(3-dimethylaminopropyl)-N-methylamino]pyrid-3-yl}-2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamidehas an IC₅₀ of approximately 0.05 μM against p38α and an IC₅₀ ofapproximately 5 μM in the Human Whole Blood test.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises an amide derivative of theFormula I, or a pharmaceutically-acceptable or in-vivo-cleavable esterthereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent compounded with an appropriate andconvenient amount of excipients which may vary from about 5 to about 98percent by weight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the Formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used. Oral administration is howeverpreferred, particularly in tablet form. Typically, unit dosage formswill contain about 1 mg to 500 mg of a compound of this invention.

According to a further aspect of the invention there is provided anamide derivative of the Formula I, or a pharmaceutically-acceptable saltor in-vivo-cleavable ester thereof, as defined hereinbefore for use in amethod of treatment of the human or animal body by therapy.

According to a further aspect of the invention there is provided the useof an amide derivative of the Formula I, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, asdefined hereinbefore in the manufacture of a medicament for use in thetreatment of diseases or medical conditions mediated by cytokines.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by cytokines which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in the treatment of diseases or medical conditions mediated by TNF,IL-1, IL-6 or IL-8.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8 whichcomprises administering to a warm-blooded animal an effective amount ofa compound of the Formula I or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof in the manufacture of a medicament foruse in the treatment of diseases or medical conditions mediated by TNF.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in inhibiting TNF, IL-1, IL-6 or IL-8.

In a further aspect the present invention provides a method ofinhibiting TNF, IL-1, IL-6 or IL-8 which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula I,or a pharmaceutically-acceptable salt or in-vivo-cleavable esterthereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in inhibiting TNF.

In a further aspect the present invention provides a method ofinhibiting TNF which comprises administering to a warm-blooded animal aneffective amount of a compound of the Formula I, or apharmaceutically-acceptable salt or in vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in the treatment of diseases or medical conditions mediated by p38kinase.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by p38 kinase which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in the production of a p38 kinase inhibitory effect.

In a further aspect the present invention provides a method of providinga p38 kinase inhibitory effect which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula I,or a pharmaceutically-acceptable salt or in-vivo-cleavable esterthereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in the treatment of rheumatoid arthritis, asthma, irritable boweldisease, multiple sclerosis, AIDS, septic shock, ischaemic heart diseaseor psoriasis.

In a further aspect the present invention provides a method of treatingrheumatoid arthritis, asthma, irritable bowel disease, multiplesclerosis, AIDS, septic shock, ischaemic heart disease or psoriasiswhich comprises administering to a warm-blooded animal an effectiveamount of a compound of the Formula I, or a pharmaceutically-acceptablesalt or in-vivo-cleavable ester thereof.

The compounds of this invention may be used in combination with otherdrugs and therapies used in the treatment of disease states which wouldbenefit from the inhibition of cytokines, in particular TNF and IL-1.For example, the compounds of the Formula I could be used in combinationwith drugs and therapies used in the treatment of rheumatoid arthritis,asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock,ischaemic heart disease, psoriasis and the other disease statesmentioned earlier in this specification.

For example, by virtue of their ability to inhibit cytokines, thecompounds of the Formula I are of value in the treatment of certaininflammatory and non-inflammatory diseases which are currently treatedwith a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug(NSAID) such as indomethacin, ketorolac, acetylsalicyclic acid,ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of acompound of the Formula I with a NSAID can result in a reduction of thequantity of the latter agent needed to produce a therapeutic effect.Thereby the likelihood of adverse side-effects from the NSAID such asgastrointestinal effects are reduced. Thus according to a furtherfeature of the invention there is provided a pharmaceutical compositionwhich comprises a compound of the Formula I, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, inconjunction or admixture with a cyclooxygenase inhibitory non-steroidalanti-inflammatory agent, and a pharmaceutically-acceptable diluent orcarrier.

The compounds of the invention may also be used with anti-inflammatoryagents such as an inhibitor of the enzyme 5-lipoxygenase.

The compounds of the Formula I may also be used in the treatment ofconditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

The compounds of the present invention may also be administered indegradative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan, Rumalon,Arteparon and glucosamine salts such as Antril.

The compounds of the Formula I may be be used in the treatment of asthmain combination with antiasthmatic agents such as bronchodilators andleukotriene antagonists.

If formulated as a fixed dose such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects ofcytokines. Thus, they are useful as pharmacological standards for use inthe development of new biological tests and in the search for newpharmacological agents.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) operations were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such as argonunless otherwise stated;

(ii) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany or high pressure liquidchromatography (HPLC) was performed on C18 reverse phase silica, forexample on a Dynamax C-18 60 Å preparative reversed-phase column;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) in general, the end-products of the Formula I have satisfactorymicroanalyses and their structures were confirmed by nuclear magneticresonance (NMR) and/or mass spectral techniques; fast-atom bombardment(FAB) mass spectral data were obtained using a Platform spectrometerand, where appropriate, either positive ion data or negative ion datawere collected; NMR chemical shift values were measured on the deltascale [proton magnetic resonance spectra were determined using a VarianGemini 2000 spectrometer operating at a field strength of 300 MHz or aBruker AM250 spectrometer operating at a field strength of 250 MHz]; thefollowing abbreviations have been used: s, singlet; d, doublet; t,triplet; m, multiplet; br, broad;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMRanalysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the Formula I were determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used:

DMF N,N-dimethylformamide

DMSO dimethylsulphoxide

THF tetrahydrofuran.

EXAMPLE 1 N-(4-propylphenyl)-5-(4-cyanobenzamido)-2-methylbenzamide

4-n-Propylaniline (0.11 g) was added to a stirred suspension of5-(4-cyanobenzamido)-2-methylbenzoyl chloride (0.224 g), triethylamine(0.21 ml) and methylene chloride (5 ml) and the resultant mixture wasstirred at ambient temperature for 16 hours. The mixture was filteredand the filtrate was evaporated. The residue was purified by columnchromatography on silica using increasingly polar mixtures of methylenechloride and methanol as eluent. There was thus obtained the titlecompound (0.049 g); NMR Spectrum: (DMSOd₆) 0.87 (t, 3H), 1.56 (m, 2H),2.33 (s, 3H), 2.48 (m, 2H), 7.13 (d, 2H), 7.28 (d, 1H), 7.63 (m, 2H),7.83 (m, 3H), 8.01 (d, 1H), 8.1 (m, 2H); Mass Spectrum: M+H⁺ 398.

The 5-(4-cyanobenzamido)-2-methylbenzoyl chloride used as a startingmaterial was prepared as follows:

4-Cyanobenzoyl chloride (4.50 g) was added to a stirred suspension ofmethyl 5-amino-2-methylbenzoate (J. Med. Chem., 1991, 34, 2176-2186; 3g), triethylamine (2.54 ml) and methylene chloride (100 ml) and theresultant mixture was stirred at ambient temperature for 16 hours. Themixture was acidified by the addition of 1N aqueous hydrochloric acidsolution and the mixture was stirred at ambient temperature for 30minutes. The resultant solid was isolated and dried under vacuum at 40°C. to give methyl 5-(4-cyanobenzamido)-2-methylbenzoate (5.32 g); NMRSpectrum: (DMSOd₆) 2.47 (s, 3H), 3.83 (s, 3H), 7.31 (d, 1H), 7.88 (d,1H), 8.0 (d, 2H), 8.1 (d, 2H), 8.27 (s, 1H), 10.57 (s, 1H); MassSpectrum: M+H⁺ 295.

A mixture of a portion (3 g) of the material so obtained, 2N aqueoussodium hydroxide solution (20.4 ml), water (10 ml) and methanol (80 ml)was stirred at ambient temperature for 16 hours. And then heated to 50°C. for 5 hours. The resultant solution was evaporated and the residuewas partitioned between ethyl acetate and water. The aqueous phase wasacidified to pH5 by the addition of 1N aqueous hydrochloric acidsolution and the resultant solid was isolated and dried under vacuum at40° C. There was thus obtained 5-(4-cyanobenzamido)-2-methylbenzoic acid(1.79 g); NMR Spectrum: (DMSOd₆) 2.45 (s, 3H), 7.24 (d, 1H), 7.84 (m,1H), 8.02 (m, 4H), 8.26 (s, 1H), 10.41 (d, 1H); Mass Spectrum: M−H⁻ 279.

Oxalyl chloride (0.104 g) was added dropwise to a stirred mixture of5-(4-cyanobenzamido)-2-methylbenzoic acid (0.21 g), DMF (a few drops)and methylene chloride (10 ml) which had been cooled to 0° C. Themixture was allowed to warm to ambient temperature and was stirred for 4hours. The mixture was evaporated to give the required starting materialwhich was used without further purification.

EXAMPLE 2

Using an analogous procedure to that described in Example 1, theappropriate benzoyl chloride was reacted with the appropriate aniline togive the compounds described in Table I.

TABLE I

No. (R¹)_(m) R³ Q Note 1 4-propyl methyl phenyl a 2 3,4-dimethoxy methylphenyl b 3 3,4-dimethoxy methyl 4-cyanophenyl c

Notes

a) The product gave the following data: NMR Spectrum: (DMSOd₆) 0.87 (t,3H), 1.52-1.56 (m, 2H), 2.32 (s, 3H) 2.48-2.53 (m, 2H), 7.13 (d, 2H),7.26 (d, 1H), 7.51-7.63 (m, 5H), 7.8 (d, 1H), 7.86 (s, 1H), 7.95 (d,2H), 10.21 (s, 1H), 10.29 (s, 1H); Mass Spectrum: M+H⁺ 373.

The 5-benzamido-2-methylbenzoyl chloride used as a starting material wasprepared from methyl 5-amino-2-methylbenzoate and benzoyl chloride usinganalogous procedures to those described in the portion of Example 1which is concerned with the preparation of starting materials. Therewere thus obtained in turn: -methyl 5-benzamido-2-methylbenzoate NMRSpectrum: (DMSOd₆) 2.43 (s, 3H), 3.83 (s, 3H), 7.29 (d, 1H), 7.49-7.61(m, 3H), 7.88 (d, 1H), 7.95 (d, 2H), 8.29 (s, 1H), 10.33 (s, 1H); MassSpectrum: M+H⁺ 270; 5-benzamido-2-methylbenzoate NMR Spectrum: (DMSOd₆)2.43 (s, 3H), 7.24 (d, 1H) 7.44-7.6 (m, 3H), 7.84 (d, 1H), 7.94 (d, 2H),8.25 (s, 1H), 10.39 (s, 1H), 12.80 (s, 1H); Mass Spectrum: M+H⁺ 254, and5-benzamido-2-methylbenzoyl chloride which was used without furtherpurification.

b) After the reaction mixture had been stirred at ambient temperaturefor 16 hours, the mixture was filtered and the filtrate was washed inturn with a 1N aqueous hydrochloric acid solution and a saturatedaqueous sodium bicarbonate solution. The organic phase was evaporatedand the residue was triturated under a mixture of isohexane and ethylacetate. The resultant solid was isolated, washed with diethyl ether anddried. The product so obtained gave the following data: NMR Spectrum:(DMSOd₆) 2.33 (s, 3H), 3.72 (s, 6H), 6.9 (d, 1H), 7.25 (d, 2H),7.43-7.58 (m, 4H), 7.78 (d, 1H), 7.87 (s, 1H), 7.95 (d, 2H), 10.13 (s,1H), 10.29 (s, 1H); Mass Spectrum: M+H⁺ 391.

c) After the reaction mixture had been stirred at ambient temperaturefor 16 hours, the mixture was filtered and the filtrate was washed inturn with a 1N aqueous hydrochloric acid solution and a saturatedaqueous sodium bicarbonate solution. The organic phase was evaporatedand the residue was triturated under a mixture of isohexane and ethylacetate. The resultant solid was isolated, washed with diethyl ether anddried. The product so obtained gave the following data: Mass Spectrum:M+H⁺ 416.

EXAMPLE 3N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamide

Using an analogous procedure to that described in Example 1,2-morpbolinopyridine-4-carbonyl chloride was reacted withN-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-5-amino-2-methylbenzamide.The residue was purified by column chromatography on an ion exchangecolumn (isolute SCX column from International Sorbent TechnologyLimited, Hengoed, Mid-Glamorgan, UK) using initially methanol and then a99:1 mixture of methanol and a saturated aqueous ammonium hydroxidesolution as eluent. There was thus obtained the title compound in 27%yield; Mass Spectrum: M+H⁺ 529.

The 2-morpholinopyridine-4-carbonyl chloride used as a starting materialwas prepared as follows:

2-Chloropyridine-4-carbonyl chloride (11.2 g) was added to a stirredmixture of potassium tert-butoxide (7.15 g) and THF (50 ml) which hadbeen cooled to 0° C. The mixture was allowed to warm to ambienttemperature and was stirred for 16 hours. The mixture was evaporated andthe residue was partitioned between ethyl acetate and water. The organicphase was washed with a saturated aqueous sodium bicarbonate solution,dried (MgSO₄) and evaporated. There was thus obtained tert-butyl2-chloropyridine-4-carboxylate (10.5 g); NMR Spectrum: (CDCl₃) 1.6 (s,9H), 7.72 (d, 1H), 7.82 (s, 1H), 8.51 (d, 1H).

After repetition of the previous reaction, a mixture of thepyridine-4-carboxylate so produced (18.3 g) and morpholine (30 ml) wasstirred and heated to 100° C. for 40 hours. The mixture was poured intowater and extracted with methylene chloride. The organic phase wasevaporated and the residue was purified by column chromatography onsilica using initially a 5:1 mixture of isohexane and ethyl acetate andthen a 10:3 mixture of the same solvents as eluent. There was thusobtained tert-butyl 2-morpholinopyridine-4-carboxylate (15 g); NMRSpectrum: (DMSOd₆) 1.52 (s, 9H), 3.46-3.55 (m, 4H) 3.62-3.7 (m, 4H) 7.09(d, 1H), 7.13 (s, 1H), 8.24 (d, 1H).

A mixture of the material so obtained, water (10 ml) and trifluoroaceticacid (90 ml) was stirred at ambient temperature for 3 hours. The mixturewas evaporated and the residue was triturated under a mixture ofisohexane and ethyl acetate. The resultant solid was isolated, washedwith ethyl acetate and dried to give 2-morpholinopyridine-4-carboxylicacid (13.2 g); NMR Spectrum: (DMSOd₆) 3.46-3.51 (m, 4H), 3.62-3.7 (m,4H), 7.07 (d 1H), 7.25 (s, 1H), 8.24 (d, 1H).

The material so obtained was reacted with oxalyl chloride using ananalogous procedure to that described in the last paragraph of theportion of Example 1 which is concerned with the preparation of startingmaterials. There was thus obtained 2-morpholinopyridine-4-carbonylchloride which was used without further purification.

The N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-5-amino-2-methylbenzamideused as a starting material was prepared as follows:

A mixture of 3-nitrobenzyl chloride (1 g) and N-methylpiperazine (3 ml)was stirred and heated to 100° C. for 4 hours. The mixture was cooled toambient temperature and partitioned between methylene chloride andwater. The organic phase was evaporated to give3-(4-methylpiperazin-1-ylmethyl)nitrobenzene (1.05 g); NMR Spectrum:(DMSOd₆) 2.14 (s, 3H), 2.31-2.38 (m, 8H), 3.57 (s, 2H), 7.6 (t, 1H),7.54 (d, 1H), 8.07-8.13 (m, 2H).

Iron powder (2.47 g) was added to a stirred suspension of the materialso obtained in a mixture of ethanol (30 ml), water (2 ml) and aceticacid (0.5 ml). The mixture was stirred and heated to reflux for 4 hours.The mixture was cooled to ambient temperature. Water (30 ml) was addedand the resultant mixture was basified by the addition of sodiumcarbonate. The mixture was filtered and the filtrate was evaporated. Theresidue was triturated under water. The resultant solid was isolated anddried under vacuum at 40° C. There was thus obtained3-(4-methylpiperazin-1-ylmethyl)aniline (0.51 g); NMR Spectrum: (DMSOd₆)2.11 (s, 3H), 2.24-2.36 (m, 8H), 3.28 (s, 2H), 4.92 (s, 2H), 6.37-6.41(m, 2H), 6.49 (s, 1H), 7.9 (t, 1H).

Oxalyl chloride (0.31 g) was added dropwise to a stirred mixture of2-methyl-5-nitrobenzoic acid (0.4 g), DMF (a few drops) and methylenechloride (25 ml) which had been cooled to 0° C. The mixture was allowedto warm to ambient temperature and was stirred for five hours. Themixture was evaporated to give 2-methyl-5-nitrobenzoyl chloride whichwas dissolved in methylene chloride (10 ml) and added dropwise to astirred mixture of 3-(4-methylpiperazin-1-ylmethyl)aniline (0.44 g),triethylamine (0.49 g) and methylene chloride (10 ml). The mixture wasstirred at ambient temperature for 16 hours. The mixture was washed witha saturated aqueous sodium bicarbonate solution. The organic phase wasevaporated and the residue was purified by column chromatography on anisolute SCX ion exchange column using initially methanol and then a 99:1mixture of methanol and a saturated aqueous ammonium hydroxide solutionas eluent. There was thus obtainedN-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-methyl-5-nitrobenzamide(0.46g); Mass Spectrum: M+H⁺ 369.

A mixture of the 5-nitrobenzamide so obtained, iron powder (2.79 g),water (1 ml), acetic acid (0.25 ml) and ethanol (15 ml) was stirred andheated to reflux for 5 hours. The mixture was cooled to ambienttemperature. Water (50 ml) was added and the mixture was basified by theaddition of sodium carbonate. The resultant mixture was filtered and thefiltrate was evaporated. The residue was partitioned between methylenechloride and water. The organic phase was evaporated and the residue waspurified by column chromatography on an isolute SCX ion exchange columnusing initially methanol and then a 99:1 mixture of methanol and asaturated aqueous ammonium hydroxide solution as eluent. There was thusobtainedN-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-5-amino-2-methylbenzamide(0.194 g); NMR Spectrum: (CDCl₃) 2.28 (s, 3H), 2.37 (s, 3H), 2.42-2.58(m, 8H), 3.5 (s, 2H), 3.64 (broad s, 2H), 5.29 (s, 1H), 6.67-6.81 (m,2H), 7.02 (t, 1H), 7.10 (d, 1H), 7.3-7.6 (m, 1H); Mass Spectrum: M+H⁺339.

EXAMPLE 4N-[6-(4-ethylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamide

2-Chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid (0.162 g)was added to a stirred mixture of5-amino-2-(4-ethylpiperazin-1-yl)pyridine (0.093 g),diisopropylethylamine (0.232 g),2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V) (0.176 g) and DMF (10 ml) and the mixture wasstirred at ambient temperature for 16 hours. The mixture was partitionedbetween ethyl acetate and water. The organic phase was washed with asaturated aqueous sodium bicarbonate solution and evaporated. Theresidue was triturated under a mixture of isohexane and ethyl acetate.The resultant solid was isolated and dried under vacuum at 40° C. togive the title compound (0.071 g); NMR Spectrum: (DMSOd₆) 1.02 (t, 3H),2.34 (m, 2H), 2.4-2.46 (m, 4H), 3.38-3.42 (m, 4H), 3.5-3.53 (m, 4H),3.69-3.71 (m, 4H), 6.82 (d, 1H), 7.08 (d, 2H), 7.22 (s, 1H), 7.62 (d,1H), 7.82-7.98 (m, 3H), 8.28 (d, 1H), 8.39 (s, 1H); Mass Spectrum: M+H⁺550 and 552.

The 2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid used asa starting material was prepared as follows:

Using an analogous procedure to that described in the last paragraph ofthe portion of Example 3 which is concerned with the preparation ofstarting materials, methyl 2-chloro-5-nitrobenzoate was reduced to givemethyl 5-amino-2-chlorobenzoate in 38% yleld; NMR Spectrum: (DMSOd₆)3.79 (s, 3H), 5.46 (s, 2H), 6.66 (d, 1H), 6.97 (s, 1H), 7.1 (d, 1H).

Using an analogous procedure to that described in Example 1,2-morpholinopyridine-4-carbonyl chloride was reacted with methyl5-amino-2-chlorobenzoate. The reaction product was triturated under amixture of isohexane and ethyl acetate. The resultant solid was isolatedand washed with diethyl ether. There was thus obtained methyl2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoate in 63% yield;NMR Spectrum. (DMSOd₆) 3.49-3.53 (m, 4H), 3.69-3.72 (m, 4H), 3.86 (s,3H), 7.09 (d, 1H), 7.23 (s, 1H), 7.56 (d, 1H), 7.96 (d, 1H), 8.25-8.28(m, 2H), 10.55 (s, 1H); Mass Spectrum: M+H⁺ 376 and 378.

A mixture of the methyl benzoate so obtained (3 g), 2N aqueous sodiumhydroxide solution (16 ml), water (25 ml) and methanol (100 ml) wasstirred at ambient temperature for 16 hours. The resultant solution wasevaporated and the residue was acidified to pH1 by the addition of 1Naqueous hydrochloric acid solution. Water (1 ml) and methanol (1 ml)were added and the mixture was stirred for 1 hour. The resultant solidwas isolated and dried under vacuum at 40° C. to give the requiredstarting material (2.83 g); NMR Spectrum: (DMSOd₆) 3.62-3.74 (m, 8H),7.21 (d, 1H), 7.53 (d, 1H), 7.63 (s, 1H), 8.01 (d, 1H), 8.21 (d, 1H),8.28 (s, 1H), 10.98 (s, 1H); Mass Spectrum: M−H⁻ 360 and 362.

The 5-amino-2-(4-ethylpiperazin-1-yl)pyridine used as a startingmaterial was prepared as follows:

A mixture of 2-chloro-5-nitropyridine (1 g) and N-ethylpiperazine (4 ml)was stirred and heated to 100° C. for 16 hours. The mixture was cooledto ambient temperature and poured in water. The resultant solid wasisolated, washed in turn with water and with diethyl ether and driedunder vacuum at 40° C. There was thus obtained2-(4-ethylpiperazin-1-yl)-5-nitropyridine (0.22 g); NMR Spectrum:(DMSOd₆) 1.01 (t, 3H), 2.33-2.41 (m, 2H), 2.42-2.44 (m, 4H), 3.71-3.75(m, 4H), 6.91 (d, 1H), 8.17 (d, 1H), 8.92 (s, 1H).

A mixture of the material so obtained, 10% palladium-on-carbon (0.095 g)and methanol (20 ml) was stirred under an atmosphere of hydrogen gas.After cessation of hydrogen uptake, the catalyst was removed byfiltration and the filtrate was evaporated. There was thus obtained therequired starting material (0.18 g); NMR Spectrum: (DMSOd₆) 1.0 (t, 3H),2.28-2.36 (m, 2H), 2.38-2.41 (m, 4H), 3.15-3.21 (m, 4H), 4.5 (broad s,2H), 6.58 (d, 1H), 6.85 (d, 1H), 7.57 (s, 1H); Mass Spectrum: M+H⁺ 207.

EXAMPLE 5

Using an analogous procedure to that described in Example 4, theappropriate 5-aminopyridine was reacted with2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid to give thecompounds described in Table II.

TABLE II

No. R¹ R³ Note 1 N-(2-dimethylaminoethyl)-N-methylamino chloro a 2N-(3-dimethylaminopropyl)-N-methylamino chloro b 34-methylpiperazin-1-yl chloro c 4 4-methylhomopiperazin-1-yl chloro d

Notes

a) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.4-2.49(m, 8H), 2.98 (s, 3H), 3.48-3.53 (m, 4H), 3.66-3.72 (m, 6H), 6.61 (m,1H), 7.1 (d, 1H), 7.23 (s, 1H), 7.53 (d, 1H), 7.78-7.82 (m, 1H),7.88-7.93 (m, 2H), 8.27-8.38 (m, 2H), 10.26 (s, 1H), 10.51 (s, 1H); MassSpectrum: M+H⁺ 538 and 540.

The 5-amino-2-[N-(2-dimethylaminoethyl)-N-methylamino]pyridine used as astarting material was prepared from 2-chloro-5-nitropyridine andN-(2-dimethylaminoethyl)-N-methylamine using analogous procedures tothose described in the portion of Example 4 which is concerned with thepreparation of 5-amino-2-(4-ethylpiperazin-1-yl)pyridine. The requiredstarting material gave the following data: NMR Spectrum: (DMSOd₆) 2.35(t, 2H), 2.48 (s, 6H), 2.82 (s, 3H), 3.32-3.44 (m, 6H), 6.4 (m, 1H),6.84-6.9 (m, 1H), 7.53-7.56 (m, 1H); Mass Spectrum: M+H⁺ 195.

b) The product was purified by column chromatography on an isolute SCXion exchange column using initially methanol and then a 99:1 mixture ofmethanol and a saturated aqueous ammonium hydroxide solution as eluent.The product gave the following data: Mass Spectrum: M+H⁺ 552 and 554.

The 5-amino-2-[N-(3-dimethylaminopropyl)-N-methylamino]pyridine used asa starting material was prepared from 2-chloro-5-nitropyridine andN-(3-dimethylaminopropyl)-N-methylamine using analogous procedures tothose described in the portion of Example 4 which is concerned with thepreparation of 5-amino-2-(4-ethylpiperazin-1-yl)pyridine. The requiredstarting material gave the following data: NMR Spectrum: (DMSOd₆)1.48-56 (m, 2H), 2.08 (s, 6H), 2.16 (t, 2H), 2.49 (s, 3H), 3.29-3.36 (m,2H), 4.28 (broad s, 2H), 6.37-6.42 (m, 1H), 6.84-6.9 (m, 1H), 7.53 (s,1H); Mass Spectrum: M+H⁺ 209.

c) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.19 (s,3H), 2.36-2.39 (m, 4H), 3.39-3.43 (m, 4H), 3.39-3.52 (m, 4H), 3.68-3.71(m, 4H), 6.84 (d, 1H), 7.8 (d, 1H), 7.23 (s, 1H), 7.52 (d, 1H),7.84-7.94 (m, 3H), 8.27 (d, 1H), 8.39 (s, 1H); Mass Spectrum: M+H⁺ 536and 538.

The 5-amino-2-(4-methylpiperazin-1-yl)pyridine used as a startingmaterial was prepared from 2-chloro-5-nitropyridine andN-methylpiperazine using analogous procedures to those described in theportion of Example 4 which is concerned with the preparation of5-amino-2-(4-ethylpiperazin-1-yl)pyridine. The required startingmaterial gave the following data: NMR Spectrum: (DMSOd₆) 2.26 (s, 3H),2.47-2.49 (m, 4H), 3.21-3.25 (m, 4H), 6.6 (d, 1H), 6.9 (d, 1H), 7.57 (s,1H); Mass Spectrum: M+H⁺ 193.

d) The product was purified by column chromatography on an isolute SCXion exchange column using initially methanol and then a 99:1 mixture ofmethanol and a saturated aqueous ammonium hydroxide solution as eluent.The product gave the following data: Mass Spectrum: M+H⁺ 550 and 552.

The 5-amino-2-(4-methylhomopiperazin-1-yl)pyridine used as a startingmaterial was prepared from 2-chloro-5-nitropyridine andN-methylhomopiperazin using analogous procedures to those described inthe portion of Example 4 which is concerned with the preparation of5-amino-2-(4-ethylpiperazin-1-yl)pyridine. The required startingmaterial gave the following data: Mass Spectrum: M+H⁺ 207.

EXAMPLE 6N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamide

Using an analogous procedure to that described in Example 4,3-(4-methylpiperazin-1-ylmethyl)aniline was reacted with2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid to give thetitle compound in 32% yleld; NMR Spectrum: (DMSOd₆) 2.13 (s, 3H),2.31-2.35 (m, 8H), 3.42 (s, 2H), 3.49-3.53 (m, 4H), 3.69-3.72 (m, 4H),7.02 (d, 1H), 7.1 (d, 1H), 7.22-7.3 (m, 2H), 7.57-7.65 (m, 3H),7.84-7.94 (m, 2H), 8.28 (d, 1H), 10.47 (s, 1H), 10.52 (s, 1H); MassSpectrum: M+H⁺ 549 and 551.

EXAMPLE 7 Pharmaceutical Compositions

The following illustrate representative pharmaceutical dosage forms ofthe invention as defined herein (the active ingredient being termed“Compound X”). for therapeutic or prophylactic use in humans:

TABLET I mg/tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellosesodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate3.0

TABLET II mg/tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellosesodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/v paste) 2.25Magnesium stearate 3.0

TABLET III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellosesodium 4.0 Maize starch (5% w/v paste) 0.75 Magnesium stearate 1.0

Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium 1.5

Injection I (50 mg/ml) Compound X 5.0% w/v 1 M Sodium hydroxide solution15.0% v/v 0.1 M Hydrochloric acid (to adjust pH to 7.6) Polyethyleneglycol 400 4.5% w/v Water for injection to 100%

Injection II (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v0.1 M Sodium hydroxide solution 15.0% v/v Water for injection to 100%

Injection III (1 mg/ml, buffered to pH 6) Compound X 0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 4003.5% w/v Water for injection to 100%

Aerosol I mg/ml Compound X 10.0 Sorbitan trioleate 13.5Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0

Aerosol II mg/ml Compound X 0.2 Sorbitan trioleate 0.27Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0Dichlorotetrafluoromethane 1094.0

Aerosol III mg/ml Compound X 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoromethane 191.6

Aerosol IV mg/ml Compound X 2.5 Soya lecithin 2.7 Trichlorofluoromethane67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoromethane 191.6

Ointment ml Compound X 40 mg Ethanol 300 μl Water 300 μl1-Dodecylazacycloheptan-2-one 50 μl Propylene glycol to 1 ml

Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate. The aerosol formulations (h)-(k) may beused in conjunction with standard, metered dose aerosol dispensers, andthe suspending agents sorbitan trioleate and soya lecithin may bereplaced by an alternative suspending agent such as sorbitan monooleate,sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleicacid.

What is claimed is:
 1. A compound of the Formula I

wherein X is CH and Y is N or Y is CH and X is N; m is 0, 1, 2 or 3; R¹is hydroxy, halogeno, trifluoromethyl, cyano, amino, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkoxy,(1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy, amino-(2-6C)alkoxy,(1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy,hydroxy-(2-6C)alkylamino, (1-6C)alkoxy-(2-6C)alkylamino,cyano-(1-6C)alkylamino, amino-(2-6C)alkylamino,(1-6C)alkylamino-(2-6C)alkylamino,di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,N-(1-6C)alkyl-cyano-(1-6C)alkylamino,N-(1-6C)alkyl-amino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino orN-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, or R¹ is aryl,aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy, heteroaryl,heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl-(1-6C)alkoxy,heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclyloxy orheterocyclyl-(1-6C)alkoxy, or (R¹)_(m) is a (1-3C)alkylenedioxy group,and wherein any of the R¹ substituents defined hereinbefore whichcomprises a CH₂ group which is attached to 2 carbon atoms or a CH₃ groupwhich is attached to a carbon atom may optionally bear on each said CH₂or CH₃ group a substituent selected from hydroxy, amino, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl, and whereinany aryl, heteroaryl or heterocyclyl group in a R¹ substituent mayoptionally bear 1 or 2 substituents selected from hydroxy, halogeno,(1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl; n is 0, 1,2 or 3; R² is hydroxy, halogeno, trifluoromethyl, cyano, mercapto,nitro, amino, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino or di-[(1-6C)alkyl]amino;R³ is halogeno, (1-6C)alkyl or (1-6C)alkoxy; q is 0; and Q is aryl orheteroaryl and Q is optionally substituted with 1, 2 or 3 substituentsselected from hydroxy, halogeno, trifluoromethyl, cyano, amino,(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy,amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy,di-[(1-6C)alkyl]amino-(2-6C)alkoxy, hydroxy-(2-6C)alkylamino,(1-6C)alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino,amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino,di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino,N-(1-6C)alkyl-cyano-(1-6C)alkylamino,N-(1-6C)alkyl-amino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, aryl,aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy, heteroaryl,heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl-(1-6C)alkoxy,heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclyloxy andheterocyclyl-(1-6C)alkoxy, or Q is substituted with a(1-3C)alkylenedioxy group, and wherein any of the substituents on Qdefined hereinbefore which comprises a CH₂ group which is attached to 2carbon atoms or a CH₃ group which is attached to a carbon atom mayoptionally bear on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino,di-[(1-6C)alkyl]amino and heterocyclyl, and wherein any aryl, heteroarylor heterocyclyl group in a substituent on Q may optionally bear 1 or 2substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy,carboxy, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryland aryl-(1-6C)alkyl; and wherein any aryl group within an R¹substituent or Q group is phenyl, indenyl, indanyl, naphthyl,tetrahydronaphthyl or fluorenyl, and any heteroaryl group within an R¹substituent or Q group is an aromatic 5- or 6-membered monocyclic ring,a 9- or 10-membered bicyclic ring or a 13- or 14-membered tricyclic ringeach with up to five ring heteroatoms selected from oxygen, nitrogen andsulphur, and any heterocyclyl group within an R¹ substituent or Q groupis a non-aromatic saturated or partially saturated 3- to 10-memberedmonocyclic or bicyclic ring with up to five heteroatoms selected fromoxygen, nitrogen and sulphur; or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.
 2. The compound of the Formula Iaccording to claim 1 wherein R³ is selected from halogeno and(1-6C)alkyl; or a pharmaceutically-acceptable salt or in-vivo-cleavableester thereof.
 3. The compound of the Formula I according to claim 1wherein X is CH and Y is N or Y is CH and X is N; R³ is fluoro, chloro,bromo, methyl or ethyl; m is 0, 1 or 2; R¹ is hydroxy, fluoro, chloro,bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy,amino, methylamino, ethylamino, dimethylamino, diethylamino,methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino,2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl,pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,4-methylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl,4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl,morpholinylmethyl, piperazinylmethyl, 4-ethylpiperazinylmethyl,4-acetylpiperazinylmethyl, pyrrolidinyloxy, 1-methylpyrrolidinyloxy,piperidinyloxy, 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy,3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy,2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy,3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy,3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy or3-(4-acetylpiperazinyl)propoxy; n is 0 or 1; R² is fluoro, chloro,bromo, methyl or ethyl; q is 0; and Q is phenyl, furyl, thienyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl ornaphthyridinyl which optionally bears 1 or 2 substituents selected fromhydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl,methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino,diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl,dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy,3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy,3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, pyridyl, pyridylmethyl, pyridylmethoxy,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,4-methylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl,4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl,morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl,4-acetylpiperazinylmethyl, pyrrolidinyloxy, 1-methylpyrrolidinyloxy,piperidinyloxy, 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy,3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy,2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy,3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy,3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy and3-(4-acetylpiperazinyl)propoxy; or a pharmaceutically-acceptable saltthereof.
 4. The compound of the Formula I according to claim 1 wherein Xis CH; Y is N; R³ is chloro or methyl; m is 0, 1 or 2; R¹ is hydroxy,fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl,methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino,diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino,2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy,3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or3-(4-acetylpiperazin-1-yl)propoxy; n is 0; q is 0; and Q is phenyl,2-pyridyl, 3-pyridyl or 4-pyridyl which optionally bears 1 or 2substituents selected from hydroxy, fluoro, chloro, trifluoromethyl,cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy,methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl,methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy,3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy,3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl,4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy,pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl,4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl,morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and3-(4-acetylpiperazin-1-yl)propoxy; or a pharmaceutically-acceptable saltthereof.
 5. The compound of the Formula I according to claim 1 wherein Xis CH; Y is N; R³ is chloro or methyl; m is 1; R¹ is selected fromdiethylaminomethyl, N-(3-dimethylaminopropyl)-N-methylamino,pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl,4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl,morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl,3-hydroxypyrrolidin-1-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy,2-pyrrolidin-1-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl,3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2-pyridylmethoxy; n is0; q is 0; and Q is 3-pyridyl or 4-pyridyl which bears a substituentselected from pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yland 4-methylpiperazin-1-yl; or a pharmaceutically-acceptable saltthereof.
 6. The compound of the Formula I according to claim 1 wherein Xis CH; Y is N; R³ is chloro or methyl; m is 1; R¹ isN-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-methylpiperazin-1-ylmethyl orpyrrolidin-3-yloxy; n is 0; q is 0; and Q is 2-morpholinopyrid-4-yl; ora pharmaceutically-acceptable salt thereof.
 7. The compound of theFormula I according to claim 1 wherein X is CH and Y is N or Y is CH andX is N; R³ is fluoro, chloro, bromo, methyl or ethyl; m is 0, 1 or 2; R¹is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl,ethyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino,diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino,2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl,pyridylmethoxy, 3-pyrrolinyl, pyrrolidinyl, piperidinyl,homopiperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl,4-ethylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl,4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl,morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl,homopiperazinylmethyl, 4-methylhomopiperazinylmethyl,4-acetylpiperazinylmethyl, pyrrolidinyloxy, 1-methylpyrrolidinyloxy,piperidinyloxy, 1-methylpiperidinyloxy, homopiperidinyloxy,1-methylhomopiperidinyloxy, 2-(pyrrolidinyl)ethoxy,3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy,2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy,3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy,3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy,3-(4-acetylpiperazinyl)propoxy, 3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidinylethyl)aminomethyl,3-pyrrolidinylpropylaminomethyl, 2-morpholinylethylaminomethyl,3-morpholinylpropylaminomethyl, 2-piperazinylethylaminomethyl,3-(4-methylpiperazinylpropyl)aminomethyl, pyridylmethoxy,imidazolylmethoxy, thiazolylmethoxy and 2-methylthiazolylmethoxy; n is 0or 1; R² is fluoro, chloro, bromo, methyl or ethyl; q is 0; and Q isphenyl, indenyl, indanyl, tetrahydronaphthyl, fluorenyl, furyl, thienyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl orxanthenyl which optionally bears 1 or 2 substituents selected fromhydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl,methoxy, ethoxy, propoxy, isopropoxy, cyclopentyloxy, methylenedioxy,methylamino, ethylamino, dimethylamino, diethylamino, acetamido,propionamido, methanesulphonamido, N-methylmethanesulphonamido,aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy,3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy,3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,phenyl, furyl, thienyl, pyridyl, pyridylmethyl, pyridylmethoxy,azetidinyl, 3-pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl,4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl,piperidinylmethyl, morpholinylmethyl, piperazinylmethyl,4-ethylpiperazinylmethyl, 4-acetylpiperazinylmethyl, pyrrolidinyloxy,1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy,2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy,3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy,2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy,2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy,2-(4-acetylpiperazinyl)ethoxy and 3-(4-acetylpiperazinyl)propoxy, andwherein any phenyl, furyl, thienyl, pyridyl or heterocyclyl group in asubstituent on Q may optionally bear 1 or 2 substituents selected fromfluoro, chloro, methyl and methoxy; or a pharmaceutically-acceptablesalt thereof.
 8. The compound of the Formula I according to claim 1wherein X is CH; Y is N; R³ is chloro or methyl; m is 1 or 2; R¹ ishydroxy, fluoro, chloro, methyl, ethyl, propyl, methoxy,dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,3-dimethylamino-2-hydroxypropoxy, 3-diethylamino-2-hydroxypropoxy,2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino,3-methylaminopropylamino, 2-dimethylaminoethylamino,2-diethylaminoethylamino, 3-dimethylaminopropylamino,4-dimethylaminobutylamino, 3-amino-2-hydroxypropylamino,3-dimethylamino-2-hydroxypropylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino,piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,4-(2-hydroxyethyl)piperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 1-benzylpiperidin-4-yloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-hydroxy-3-pyrrolidin-1-ylpropoxy, 2-hydroxy-3-piperidinopropoxy,2-hydroxy-3-morpholinopropoxy, piperidin-4-ylamino,1-methylpiperidin-4-ylamino, 1-benzylpiperidin-4-ylamino,2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1ylpropylamino,2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino,3-piperidinopropylamino, 2-piperazin-1-ylethylamino,3-piperazin-1-ylpropylamino, 2-(4-methylpiperazin-1-yl)ethylamino,3-(4-methylpiperazin-1-yl)propylamino,2-(1-methylpyrrolidin-2-yl)ethylamino,3-(1-methylpyrrolidin-2-yl)propylamino, 2-dimethylaminoethylaminomethyl,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl,3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl or 2-pyridylmethoxy; n is 0;q is 0; and Q is 2-pyridyl, 3-pyridyl or 4-pyridyl which bears asubstituent selected from pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,2-hydroxymethylpyrrolidin-1-yl, morpholino, piperidino,4-hydroxypiperidin-1-yl, piperazin-1-yl and 4-methylpiperazin-1-yl; or apharmaceutically-acceptable salt thereof.
 9. The compound of the FormulaI according to claim 1 wherein X is CH; Y is N; R³ is chloro or methyl;m is 1; R¹ is selected from diethylaminomethyl,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino,piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,2-piperidinoethoxy, 2-morpholinoethoxy,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-imethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl,3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2-pyridylmethoxy; n is0; q is 0; and Q is 3-pyridyl or 4-pyridyl which bears a substituentselected from pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yland 4-methylpiperazin-1-yl; or a pharmaceutically-acceptable saltthereof.
 10. The compound of the Formula I according to claim 1 whereinX is CH; Y is N; R³ is chloro or methyl; m is 1; R¹ is selected fromdiethylaminomethyl, N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, 3-pyrrolin-1-yl,pyrrolidin-1-yl, morpholino, piperidino, homopiperidin-1-yl,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl,homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,N-methylpiperidin-4-yloxy, homopiperidin-4-yloxy,N-methylhomopiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,2-piperidinoethoxy, 2-morpholinoethoxy,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl,3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl, 2-pyridylmethoxy,4-thiazolylmethoxy and 2-methylthiazol-4-ylmethoxy; n is 0; q is 0; andQ is phenyl which bears 1 or 2 substituents selected from fluoro,chloro, trifluoromethyl, methoxy, cyclopentyloxy, acetamido,N-methylmethanesulphonamido, 2-furyl, azetidin-1-yl, 3-pyrrolin-1-yl,pyrrolidin-1-yl, morpholino, piperidino, homopiperidino, piperazin-1-yl,homopiperazin-1-yl, 4-methylpiperazin-1-yl and4-methylhomopiperazin-1-yl, or Q is 1-fluorenyl or 4-dibenzofuranyl, orQ is 3-pyridyl or 4-pyridyl which bears a substituent selected fromazetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino,homopiperidino, piperazin-1-yl, homopiperazin-1-yl,4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl; or apharmaceutically-acceptable salt thereof.
 11. The compound of theFormula I according to claim 1 wherein X is CH; Y is N; R³ is chloro ormethyl; m is 1; R¹ is N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or4-methylpiperazin-1-ylmethyl; n is 0; q is 0; and Q is2-(pyrrolidin-1-yl)pyrid-4-yl, 2-(3-pyrrolin-1-yl)pyrid-4-yl,2-piperidinopyrid-4-yl, 2-morpholinopyrid-4-yl, 1-fluorenyl,dibenzofuran-4-yl, 3-acetamidophenyl or 3-(2-furyl)phenyl; or apharmaceutically-acceptable salt thereof.
 12. The compound of theFormula I according to claim 1 wherein X is CH; Y is N; R³ is chloro ormethyl; m is 1; R¹ is N-(3-dimethylaminopropyl)-N-methylamino,4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or4-methylpiperazin-1-ylmethyl; n is 0; q is 0; and Q is2-morpholinopyrid-4-yl; or a pharmaceutically-acceptable salt thereof.13. The compound of the Formula I according to claim 1 selected from:N-[6-(4-ethylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamide,N-[6-(4-methylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamideandN-{6-[N-(3-dimethylaminopropyl)-N-methylamino]pyrid-3-yl}-2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzamide;or a pharmaceutically-acceptable salt thereof.
 14. A process for thepreparation of an amide derivative of the Formula I, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof,according to claim 1 which comprises: (a) reacting an aniline of theFormula II

 with a benzoic acid of the Formula III, or an activated derivativethereof,

 under standard amide bond forming conditions, wherein variable groupsare as defined in claim 1 and wherein any functional group is protected,if necessary, and: (i) removing any protecting groups; (ii) optionallyforming a pharmaceutically-acceptable salt or in-vivo-cleavable ester;(b) reacting an aniline of the Formula VI

 with a carboxylic acid of the Formula V, or a reactive derivativethereof,

 under standard amide bond forming conditions, wherein variable groupsare as defined in claim 1 and wherein any functional group is protectedif necessary, and: (i) removing any protecting groups; and (ii)optionally forming a pharmaceutically-acceptable salt orin-vivo-cleavable ester; (c) an amide derivative of the Formula Iwherein R¹ or a substituent on Q is (1-6C)alkoxy or substituted(1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylamino, di-[(1-6C)alkyl]aminoor substituted (1-6C)alkylamino may be prepared by the alkylation,conveniently in the presence of a suitable base, of an amide derivativeof the Formula I wherein R¹ or a substituent on Q is hydroxy, mercaptoor amino as appropriate; (d) an amide derivative of the Formula Iwherein a substituent on Q is amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, substituted (1-6C)alkylamino, substitutedN-(1-6C)alkyl-(2-6C)alkylamino or a N-linked heterocyclyl group may beprepared by the reaction, conveniently in the presence of a suitablebase, of an amide derivative of the Formula I wherein a substituent on Qis a suitable leaving group with an appropriate amine; (e) an amidederivative of the Formula I wherein R¹ or a substituent on Q is(1-6C)alkanoylamino or substituted (2-6C)alkanoylamino may be preparedby the acylation of a compound of the Formula I wherein R¹ or asubstituent on Q is amino; (f) an amide derivative of the Formula Iwherein R¹ or a substituent on Q is (1-6C)alkanesulphonylamino may beprepared by the reaction of a compound of the Formula I wherein R¹ or asubstituent on Q is amino with a (1-6C)alkanesulphonic acid, or anactivated derivative thereof; (g) an amide derivative of the Formula Iwherein R¹ or a substituent on Q is carboxy, carboxy-(1-6C)alkyl,carboxy-(1-6C)alkoxy, carboxy-(1-6C)alkylamino,N-(1-6C)alkyl-carboxy-(1-6C)alkylamino or carboxy-(2-6C)alkanoylaminomay be prepared by the cleavage of a compound of the Formula I whereinR¹ or a substituent on Q is (1-6C)alkoxycarbonyl,(1-6C)alkoxycarbonyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkoxy,(1-6C)alkoxycarbonyl-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino or(1-6C)alkoxycarbonyl-(2-6C)alkanoylamino as appropriate; or (h) an amidederivative of the Formula I wherein R¹ is amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or aheterocyclyl-(1-6C)alkyl group may be prepared by the reaction,conveniently in the presence of a suitable base, of a compound of theFormula IX

 wherein X, Y, R², R³, n, q and Q have any of the meanings defined inclaim 1 and Z is a suitable leaving group with an appropriate amine orheterocycle.
 15. A pharmaceutical composition which comprises a compoundof the Formula I, or a pharmaceutically-acceptable or in-vivo-cleavableester thereof, according to claim 1 in association with apharmaceutically-acceptable diluent or carrier.
 16. A method of treatinga disease or medical condition mediated by the production or effect ofcytokines, which method comprises administering to a warm-blooded animalin need thereof a cytokine inhibiting amount of a compound of theFormula I, or a pharmaceutically-acceptable salt or in-vivo-cleavableester thereof, according to claim 1.